Benzenesulfonamides and the use thereof to modulate the activity of endothelin

ABSTRACT

N-(5-isoxazolyl)benzenesulfonamides and N-(3-isoxazolyl)benzenesulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(5-isoxazolyl)biphenylsulfonamides and N-(3-isoxazolyl)biphenylsulfonamides and methods for inhibiting the binding of an endothelin peptide to an endothelin receptor or increasing the activity of endothelin peptides by contacting the receptor with a sulfonamide are provided. N-isoxzolyl-4-biphenylsulfonamides are particularly preferred. These compounds exhibit activity as endothelin receptor B antagonists. Methods for treating endothelin-mediated disorders, particularly inflammatory diseases, such as asthma, by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/439,802 filed Nov. 12, 1999, allowed which is a continuation of U.S.application Ser. No. 08/730,633 filed Dec. 6, 1996, now U.S. Pat. No.6,030,991, which is a continuation of U.S. application Ser. No.08/416,199 filed Apr. 4, 1995, ABN which is a continuation-in-part ofU.S. application Ser. No. 08/247,072, filed May 20, 1994, now U.S. Pat.No. 5,571,821 and a continuation in part of U.S. application Ser. No.08/222,287 filed Apr. 5, 1994, now U.S. Pat. No. 5,591,761 and acontinuation in part of U.S. application Ser. No. 08/142,159 filed Oct.21, 1993, now U.S. Pat. No. 5,464,853, and a continuation in part ofU.S. application Ser. No. 08/142,552 filed Oct. 21, 1993, now U.S. Pat.No. 5,514,691 and a continuation in part of U.S. application Ser. No.08/100,565 filed Jul. 30, 1993, now abandoned; and a continuation inpart of U.S. application Ser. No. 08/100,125 filed Jul. 30, 1993, nowabandoned; and a continuation in part of U.S. application Ser. No.08/065,202, filed May 20, 1993, now abandoned.

The subject matter of each of U.S. application Ser. Nos. 09/439,802,08/730,633, 08/416,199, 08/247,072, 08/222,287, 08/142,159, 08/142,552,08/142,631, 08/100,565, 08/100,125 and 08/065,202 is incorporated hereinin its entirety.

FIELD OF THE INVENTION

The present invention relates to the compounds that modulate theactivity of the endothelin family of peptides. In particular, theinvention relates to the use of sulfonamides and sulfonamide pro-drugsas endothelin agonists and antagonists.

BACKGROUND OF THE INVENTION

The vascular endothelium releases a variety of vasoactive substances,including the endothelium-derived vasoconstrictor peptide, endothelin(ET) (see, e.g., Vanhoutte et al. (1986) Annual Rev. Physiol. 48:307-320; Furchgott and Zawadski (1980) Nature 288: 373-376). Endothelin,which was originally identified in the culture supernatant of porcineaortic endothelial cells (see, Yanagisawa et aL (1988) Nature 332:411-415), is a potent twenty-one amino acid peptide vasoconstrictor. Itis the most potent vasopressor known and is produced by numerous celltypes, including the cells of the endothelium, trachea, kidney andbrain. Endothelin is synthesized as a two hundred and three amino acidprecursor preproendothelin that contains a signal sequence which iscleaved by an endogenous protease to produce a thirty-eight (human) orthirty-nine (porcine) amino acid peptide. This intermediate, referred toas big endothelin, is processed in vivo to the mature biologicallyactive form by a putative endothelin-converting enzyme (ECE) thatappears to be a metal-dependent neutral protease (see, eq., Kashiwabaraet al. (1989) FEBS Lttrs. 247: 337-340). Cleavage is required forinduction of physiological responses (see, e.g., von Geldern et al.(1991) Peptide Res. 4: 32-35). In porcine aortic endothelial cells, thethirty-nine amino acid intermediate, big endothelin, is hydrolyzed atthe Trp²¹-Val²² bond to generate endothelin-1 and a C-terminal fragment.A similar cleavage occurs in human cells from a thirty-eight amino acidintermediate. Three distinct endothelin isopeptides, endothelin-1,endothelin-2 and endothelin-3, that exhibit potent vasoconstrictoractivity have been identified.

The family of three isopeptides endothelin-1, endothelin-2 andendothelin-3 are encoded by a family of three genes (see, Inoue et al.(1989) Proc. Natl. Acad. Sci. USA 86: 2863-2867; see, also Saida et al.(1989) J. Biol. Chem. 264: 14613-14616). The nucleotide sequences of thethree human genes are highly conserved within the region encoding themature 21 amino acid peptides and the C-terminal portions of thepeptides are identical. Endothelin-2 is (Trp⁶,Leu⁷) endothelin-1 andendothelin-3 is (Thr²,Phe⁴,Thr⁵,Tyr⁶,Lys⁷,Tyr¹⁴) endothelin-1. Thesepeptides are, thus, highly conserved at the C-terminal ends.

Release of endothelins from cultured endothelial cells is modulated by avariety of chemical and physical stimuli and appears to be regulated atthe level of transcription and/or translation. Expression of the geneencoding endothelin-1 is increased by chemical stimuli, includingadrenaline, thrombin and Ca²⁺ ionophore. The production and release ofendothelin from the endothelium is stimulated by angiotensin II,vasopressin, endotoxin, cyclosporine and other factors (see, Brooks etal. (1991) Eur. J. Pharm. 194:115-117), and is inhibited by nitricoxide. Endothelial cells appear to secrete short-livedendothelium-derived relaxing factors (EDRF), including nitric oxide or arelated substance (Palmer et al. (1987) Nature 327: 524-526), whenstimulated by vasoactive agents, such as acetylcholine and bradykinin.Endothelin-induced vasoconstriction is also attenuated by atrialnatriuretic peptide (ANP).

The endothelin peptides exhibit numerous biological activities in vitroand in vivo. Endothelin provokes a strong and sustained vasoconstrictionin vivo in rats and in isolated vascular smooth muscle preparations; italso provokes the release of eicosanoids and endothelium-derivedrelaxing factor (EDRF) from perfused vascular beds. Intravenousadministration of endothelin-1 and in vitro addition to vascular andother smooth muscle tissues produce long-lasting pressor effects andcontraction, respectively (see, e.g., Bolger et al. (1991) Can. J.Physiol. Pharmacol. 69: 406-413). In isolated vascular strips, forexample, endothelin-1 is a potent (EC₅₀=4×10⁻¹⁰ M), slow acting, butpersistent, contractile agent. In vivo, a single dose elevates bloodpressure in about twenty to thirty minutes. Endothelin-inducedvasoconstriction is not affected by antagonists to knownneurotransmitters or hormonal factors, but is abolished by calciumchannel antagonists. The effect of calcium channel antagonists, however,is most likely the result of inhibition of calcium influx, since calciuminflux appears to be required for the long-lasting contractile responseto endothelin.

Endothelin also mediates renin release, stimulates ANP release andinduces a positive inotropic action in guinea pig atria. In the lung,endothelin-1 acts as a potent bronchoconstrictor (Maggi et al. (1989)Eur. J. Pharmacol. 160: 179-182). Endothelin increases renal vascularresistance, decreases renal blood flow, and decreases glomerularfiltrate rate. It is a potent mitogen for glomerular mesangial cells andinvokes the phosphoinoside cascade in such cells (Simonson et al. (1990)J. Clin. Invest. 85: 790-797).

There are specific high affinity binding sites (dissociation constantsin the range of 2-6×10⁻¹⁰ M) for the endothelins in the vascular systemand in other tissues, including the intestine, heart, lungs, kidneys,spleen, adrenal glands and brain. Binding is not inhibited bycatecholamines, vasoactive peptides, neurotoxins or calcium channelantagonists. Endothelin binds and interacts with receptor sites that aredistinct from other autonomic receptors and voltage dependent calciumchannels. Competitive binding studies indicate that there are multipleclasses of receptors with different affinities for the endothelinisopeptides. The sarafotoxins, a group of peptide toxins from the venomof the snake Atractaspis eingadensis that cause severe coronaryvasospasm in snake bite victims, have structural and functional homologyto endothelin-1 and bind competitively to the same cardiac membranereceptors (Kloog et al. (1989) Trends Pharmacol. Sci. 10: 212-214).

Two distinct endothelin receptors, designated ET_(A) and ET_(B), havebeen identified and DNA clones encoding each receptor have been isolated(Arai et al. (1990) Nature 348: 730-732; Sakurai et al. (1990) Nature348: 732-735). Based on the amino acid sequences of the proteins encodedby the cloned DNA, it appears that each receptor contains seven membranespanning domains and exhibits structural similarity to G-protein-coupledmembrane proteins. Messenger RNA encoding both receptors has beendetected in a variety of tissues, including heart, lung, kidney andbrain. The distribution of receptor subtypes is tissue specific (Martinet al. (1989) Biochem. Biophys. Res. Commun. 162: 130-137). ET_(A)receptors appear to be selective for endothelin-1 and are predominant incardiovascular tissues. ET_(B) receptors are predominant innoncardiovascular tissues, including the central nervous system andkidney, and interact with the three endothelin isopeptides (Sakurai etal. (1990) Nature 348: 732-734). In addition, ET_(A) receptors occur onvascular smooth muscle, are linked to vasoconstriction and have beenassociated with cardiovascular, renal and central nervous systemdiseases; whereas ET_(B) receptors are located on the vascularendothelium, linked to vasodilation (Takayanagi et al. (1991) FEBSLttrs. 282: 103-106) and have been associated with bronchoconstrictivedisorders.

By virtue of the distribution of receptor types and the differentialaffinity of each isopeptide for each receptor type, the activity of theendothelin isopeptides varies in different tissues. For example,endothelin-1 inhibits ¹²⁵I-labelled endothelin-1 binding incardiovascular tissues forty to seven hundred times more potently thanendothelin-3. ¹²⁵I-labelled endothelin-1 binding in non-cardiovasculartissues, such as kidney, adrenal gland, and cerebellum, is inhibited tothe same extent by endothelin-1 and endothelin-3, which indicates thatET_(A) receptors predominate in cardiovascular tissues and ET_(B)receptors predominate in non-cardiovascular tissues.

Endothelin plasma levels are elevated in certain disease states (see,eq, International PCT Application WO 94/27979, and U.S. Pat. No.5,382,569, which disclosures are herein incorporated in their entiretyby reference). Endothelin-1 plasma levels in healthy individuals, asmeasured by radioimmunoassay (RIA), are about 0.26-5 pg/ml. Blood levelsof endothelin-1 and its precursor, big endothelin, are elevated inshock, myocardial infarction, vasospastic angina, kidney failure and avariety of connective tissue disorders. In patients undergoinghemodialysis or kidney transplantation or suffering from cardiogenicshock, myocardial infarction or pulmonary hypertension levels are ashigh as 35 pg/mi have been observed (see, Stewart et al. (1991) AnnalsInternal Med. 114: 464-469). Because endothelin is likely to be a local,rather than a systemic, regulating factor, it is probable that thelevels of endothelin at the endothelium/smooth muscle interface are muchhigher than circulating levels.

Elevated levels of endothelin have also been measured in patientssuffering from ischemic heart disease (Yasuda et al. (1990) Amer. HeartJ. 119:801-806, Ray et al. (1992) Br. Heart J. 67:383-386). Circulatingand tissue endothelin immunoreactivity is increased more than twofold inpatients with advanced atherosclerosis (Lerman et al. (1991) New Engl.J. Med. 325:997-1001). Increased endothelin immunoreactivity has alsobeen associated with Buerger's disease (Kanno et al. (1990) J. Amer.Med. Assoc. 264:2868) and Raynaud's phenomenon (Zamora et al. (1990)Lancet 336 1144-1147). Increased circulating endothelin levels wereobserved in patients who underwent percutaneous transluminal coronaryangioplasty (PTCA) (Tahara et al. (1991) Metab. Clin. Exp. 40:1235-1237;Sanjay et al. (1991) Circulation 84(Suppl. 4):726), and in individuals(Miyauchi et al. (1992) Jpn. J. Pharmacol.58:279P; Stewart et al. (1991)Ann.Internal Medicine 114:464-469) with pulmonary hypertension. Thus,there is clinical human data supporting the states.

Because endothelin is associated with certain disease states and isimplicated in numerous physiological effects, compounds that caninterfere with or potentiate endothelin-associated activities, such asendothelin-receptor interaction and vasoconstrictor activity, are ofinterest. Compounds that exhibit endothelin antagonistic activity havebeen identified. For example, a fermentation product of Streptomycesmisakiensis, designated BE-18257B, has been identified as an ET_(A)receptor antagonist. BE-18257B is a cyclic pentapeptide,cyclo(D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp), which inhibits ¹²⁵I-labelledendothelin-1 binding in cardiovascular tissues in aconcentration-dependent manner (IC₅₀ 1.4 μM in aortic smooth muscle, 0.8μM in ventricle membranes and 0.5 μM in cultured aortic smooth musclecells), but fails to inhibit binding to receptors in tissues in whichET_(B) receptors predominate at concentrations up to 100 μM. Cyclicpentapeptides related to BE-18257B, such ascyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), have been synthesized andshown to exhibit activity as ET_(A) receptor antagonists (see, U.S. Pat.No. 5,114,918 to Ishikawa et al.; see, also, EP A1 0 436 189 to BANYUPHARMACEUTICAL CO., LTD (Oct. 7, 1991)). Studies that measure theinhibition by these cyclic peptides of endothelin-1 binding toendothelin-specific receptors indicate that these cyclic peptides bindpreferentially to ET_(A) receptors. Other peptide and non-peptidicET_(A) antagonists have been identified (see, e.g., U.S. Pat. Nos.5,352,800, 5,334,598, 5,352,659, 5,248,807, 5,240,910, 5,198,548,5,187,195, 5,082,838). These include other cyclic peptides,acyltripeptides, hexapeptide analogs, certain anthraquinone derivatives,indanecarboxylic acids, certain N-pyrimidinylbenzenesulfonamides,certain benzenesulfonamides, and certain naphthalenesulfonamides(Nakajima et al. (1991) J. Antibiot. 44:1348-1356; Miyata et al. (1992)J. Antibiot. 45:74-8; Ishikawa et al. (1992) J.Med. Chem. 35:2139-2142;U.S. Pat. No. 5,114,918 to Ishikawa et al.; EP A1 0 569 193; EP A1 0 558258; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (Oct. 7, 1991);Canadian Patent Application 2,067,288; Canadian Patent Application2,071,193; U.S. Pat. No. 5,208,243; U.S. Pat. No. 5,270,313; Cody et al.(1993) Med. Chem. Res. 3:154-162; Miyata et al. (1992) J. Antibiot45:1041-1046; Miyata et al. (1992) J. Antibiot 45:1029-1040, Fujimoto etal. (1992) FEBS Lett. 305:41-44; Oshashi et al. (1002) J. Antibiot45:1684-1685; EP A1 0 496 452; Clozel et al. (1993) Nature 365:759-761;International Patent Application WO 93/08799; Nishikibe et al. (1993)Life Sci. 52:717-724; and Benigni et al. (1993) Kidney Int. 44:440-444).In general, the identified compounds have activities in in vitro assaysas ET_(A) antagonists at concentrations on the order of about 50-100 μMor less. A number of such compounds have also been shown to possessactivity in in vivo animal models. Very few, if any, selective ET_(B)antagonists have been identified.

Endothelin Antagonists and Agonists as Therapeutic Agents

It has been recognized that compounds that exhibit activity at IC₅₀ orEC₅₀ concentrations on the order of 10⁻⁴ or lower in standard in vitroassays that assess endothelin antagonist or agonist activity havepharmacological utility (see, eg., U.S. Pat. Nos. 5,352,800, 5,334,598,5,352,659, 5,248,807, 5,240,910, 5,198,548, 5,187,195, 5,082,838). Byvirtue of this activity, such compounds are considered to be useful forthe treatment of hypertension such as peripheral circulatory failure,heart disease such as angina pectoris, cardiomyopathy, arteriosclerosis,myocardial infarction, pulmonary hypertension, vasospasm, vascularrestenosis, Raynaud's disease, cerebral stroke such as cerebral arterialspasm, cerebral ischemia, late phase cerebral spasm after subarachnoidhemorrhage, asthma, bronchoconstriction, renal failure, particularlypost-ischemic renal failure, cyclosporine nephrotoxicity such as acuterenal failure, colitis, as well as other inflammatory diseases,endotoxic shock caused by or associated with endothelin, and otherdiseases in which endothelin has been implicated.

Thus, in view of the numerous physiological effects of endothelin andits association with certain diseases, endothelin is believed to play acritical role in these pathophysiological conditions (see, em, Saito etal. (1990) Hypertension 15: 734-738; Tomita et al. (1989) N. Engl. J.Med. 321: 1127; Kurihara et al. (1989) J. Cardiovasc. Pharmacol.13(Suppl. 5): S13-S17; Doherty (1992) J. Med. Chem. 35: 1493-1508; Morelet al. (1989) Eur. J. Pharmacol. 167: 427-428). More detailed knowledgeof the function and structure of the endothelin peptide family shouldprovide insight in the progression and treatment of such conditions.

To aid in gaining further understanding of and to develop treatments forendothelin-mediated or related disorders, there is a need to identifycompounds that modulate or alter endothelin activity. Identification ofcompounds that modulate endothelin activity, such as compounds that actas specific antagonists or agonists, may not only aid in elucidating thefunction of endothelin, but may yield in therapeutically usefulcompounds. In particular, compounds that specifically interfere with theinteraction of endothelin peptides with ET_(A), ET_(B) or otherreceptors should be useful in identifying essential characteristics ofendothelin peptides, should aid in the design of therapeutic agents, andmay be useful as disease specific therapeutic agents.

Therefore, it is an object herein to provide compounds that have theability to modulate the biological activity of one or more of theendothelin isopeptides. It is another object to provide compounds thathave use as specific endothelin antagonists. It is of particularinterest herein to provide compounds that selectively interact withET_(B) receptors. It is also an object to use compounds thatspecifically interact with or inhibit the interaction of endothelinpeptides with ET_(A) or ET_(B) receptors. Such compounds should beuseful as therapeutic agents for the treatment of endothelin-mediateddiseases and disorders and also for the identification of endothelinreceptor subtypes.

SUMMARY OF THE INVENTION

Sulfonamides and methods for modulating the interaction of an endothelinpeptide with ET_(A) and/or ET_(B) receptors are provided. In particular,sulfonamides and methods for inhibiting the binding of an endothelinpeptide to ET_(A) or ET_(B) receptors are provided. Sulfonamides thatact as endothelin peptide agonists with respect to ET_(A) or ET_(B)receptors are also provided. Among the compounds provided herein arethose that are particularly active as ET_(B) antagonists.

The methods are effected by contacting endothelin receptors with one ormore sulfonamides prior to, simultaneously with, or subsequent tocontacting the receptors with an endothelin peptide. The sulfonamidesare substituted or unsubstituted monocyclic or polycyclic aromatic orheteroaromatic sulfonamides, such as benzene sulfonamides, particularlybiphenyl sulfonamides, naphthalene sulfonamides, and fused tricyclicring sulfonamides.

The sulfonamides have formula I:

in which Ar¹ is a substituted or unsubstituted aryl group with one ormore substituents, including an alkyl group, an aryl group, asubstituted aryl group, a nitro group, an amino group or a halide or isan alkyl group. In particular, Ar¹ is alkyl or is a five or six memberedsubstituted or unsubstituted aromatic or heteroaromatic rings,including, 3- or 5-isoxazolyl, thiazolyl such as 2-thiazolyl,pyrimidinyl such as 2-pyrimidinyl, pyridazinyl, and unsubstituted orsubstituted benzene groups, including aryloxy substituted benzene groupsor is a bicyclic or tricyclic ring.

Ar² is any group such that the resulting sulfonamide inhibits binding by50%, compared to binding in the absence of the sulfonamide, of anendothelin peptide to an endothelin receptor at a concentration of thesulfonamide of less than about 100 μM, except that Ar² is not phenyl,2-biphenyl or naphthyl unless R¹ is a halide or higher alkyl or unlessit is a biphenyl, other than a 2-biphenyl, and the substituent at the 2(and/or 6 position)s on the phenyl linked to the sulfonamide ishydrogen.

Ar¹ is, in certain embodiments, selected from groups such as:

and R is selected from H, NH₂, halide, pseudohalide, alkylalkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl,alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio,haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, areunsubstituted or substituted with any of the preceding groups, andunsubstituted or substituted with any of the preceding groups, andstraight or branched chains of from about 1 up to about 10-12 carbons,preferably, 1 to about 5 or 6 carbons. R is preferably H, NH₂, halide,CH₃, CH₃O or another aromatic group.

In the embodiments described in detail herein, Ar¹ is generally anisoxazole and the compounds are represented by the formulae II:

in which R¹ and R² are either (i), (ii) or (iii) as follows:

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,arylcarbonyl, formyl, substituted or unsubstituted amido, substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionscontain from 1 up to about 14 carbon atoms and are either straight orbranched chains or cyclic, and the aryl portions contain from about 4 toabout 16 carbons, except that R² is not halide or pseudohalide; or,

(ii) R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or,

(iii) R¹ and R² together form 1,3-butadienyl, and with the proviso thatAr² is not 2-biphenyl, naphthyl or phenyl, other than certain3-biphenyls or 4-biphenyls, unless R¹ is a halide or higher (C₈-C₁₅,preferably C₉-C₁₃) alkyl. R¹ is more preferably bromide or chloride,methyl or ethyl or (C₉-C₁₃)alkyl. In the most active compounds providedherein, as evidenced by in vitro binding assays, R¹ is bromide orchloride or, in instances in which ET_(B) selectivity is desired, C₉-C₁₃alkyl.

In other embodiments herein, Ar¹ is pyridazinyl, particularlyN-3-pyridazinyl sulfonamides, in which the pyridazinyl group isunsubstituted or substituted with one or more substituents selected fromR.

In the embodiments described in detail herein, Ar² is naphthyl, phenyl,including biphenyl or a group that is a derivative of or analog, asdescribed below, of a biphenyl group, and Ar¹ is preferablyN-(5-isoxazolyl) or N-(3-isoxazolyl) or N-pyridazinyl, preferablyN-3-pyridazinyl.

In the preferred compounds herein, R² is preferably, selected from amongalkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide or H; andR¹ is halide, lower alkyl, or higher (C₈-C₁₅, preferably C₉-C₁₃) alkyl,except: (a) when Ar² is phenyl and R⁴, R⁵, R⁶ and R⁷ are hydrogen, R³isnot, NO₂, NH₂ or lower alkyl, unless R¹ is higher alkyl; and (b) if Ar²is naphthyl or if Ar² is phenyl, or if Ar² is 2-biphenyl or if Ar² is3-biphenyl in which R⁴ and R⁵ are other than hydrogen, then R¹ is halideor higher alkyl (C₈H₁₇—C₁₅H₂₉), preferably C₉H₁₇—C₁₃H₂₇).

In particular embodiments disclosed herein, Ar² is a group of formulaeIII:

in which:

n is 0 to 10, preferably 0 to 3, more preferably 0 or 1, most preferably0;

R³, R⁴, R⁵, R⁶, and R⁷ are selected from (i), (ii), (iii), (iv) or (v)with the proviso that: (a) when Ar² is phenyl and R⁴, R⁵, R⁶ and R⁷ arehydrogen, R³ is not NO₂, NH₂ or lower alkyl, unless R¹ is higher alkyl;(b) if Ar² is naphthyl or if Ar² is phenyl, or if Ar² is 2-biphenyl orif Ar² is 3-biphenyl in which R⁴ and R⁵ are other than hydrogen, then R¹is halide or higher (C₈-C₁₅, preferably C₉-C₁₃) alkyl:

(i) R³, R⁴, R⁵, R⁶, and R⁷ are each selected independently from among H,NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl,formyl, substituted or unsubstituted amido, substituted or unsubstitutedureido, where the alkyl, alkenyl, alkynyl portions are straight orbranched chains of from about 1 up to about 10 carbons, preferably, 1 toabout 5 or 6 carbons and the aryl portions contain from 3 up to about 10carbons, preferably 6 carbons; or, alternatively,

(ii) R⁴ and R⁷ together are substituted or unsubstituted 1,3-butadienyl,4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl,1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and R³, R⁵ and R⁶are as defined in (i) above; or alternatively,

(iii) R⁷ and R³ together are substituted or unsubstituted1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl,1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and n, X, R⁴, R⁵and R⁶ are as defined in (i) above; or

(iv) R³, R⁵, and R⁷ are H or as defined in (i); and R⁴ and R⁶ are eachindependently selected from alkyl, alkoxy, halide aminoalkyl,dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1to 10, preferably 1 to 6 carbons, and are straight or branched chains;or

(v) any two of R³, R⁴, R⁵, R⁶, and R⁷, which are each selected as in (i)form fused carbocyclic or heterocyclic rings.

Thus, in the compounds provided herein Ar² is selected from amongphenyl, biphenyl, naphthyl, and bicyclic and tricyclic fused carbocyclicand heterocyclic rings, and other such groups.

Selected isoxazolyl-benzenesulfonamides andisoxazolyl-naphthalenesulfonamides in which the isoxazole is other thana 4-haloisoxazole are also provided. Such selected compounds, includingN-isoxazolylbenzenesulfonamides and N-isoxazolyinaphthalenesulfonamidesin which the substituent at the 4 position on the isoxazolyl group ishigher alkyl, such as C₉H₁₉ to C₁₃H₂₇ are also provided. These compoundshave enhanced ET_(B) affinity compared to corresponding compounds inwhich the substituent at the 4 position is lower alkyl or other groups,such as pseudohalide, halide, alkylaryl, aryl, lower alkyl, carboxamide,alkoxy, and others.

In embodiments in which Ar² is biphenyl, one of R³, R⁴, R⁵, R⁶ and R⁷ isphenyl, which is substituted or is unsubstituted with substituents suchas Z¹-Z⁵ in which each Z is independently selected from hydrogen,halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ in which n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶ and CONR¹²R¹⁶; and R¹² and R¹⁶ are eachindependently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; and

the others of R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected fromamong H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl,alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl,alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynylportions are straight or branched chains of from about 1 up to about 10carbons, preferably, 1 to about 5 or 6 carbons and the aryl portionscontain from 3 up to about 10 carbons, preferably 6 carbons; or,alternatively, with the proviso that: if Ar² is 2-biphenyl or if Ar² is3-biphenyl in which R⁴ and R⁵ are other than hydrogen, then R¹ is halideor higher (C₈-C₁₅, preferably C₉-C₁₃) alkyl. In other embodiments, ifAr² is 4-biphenyl and R⁴ and/or R⁵ are other hydrogen, then R¹ is halideor higher (C₈-C₁₅, preferably C₉-C₁₃) alkyl.

Z is preferably selected from:

(i) hydrogen, OH, NH₂, NO₂, alkyl, haloalkyl, halide, pseudohalide,alkoxy, alkoxyalkyl, NR¹¹, in which R¹¹ is selected from among H, astraight or branched carbon chain, preferably containing 1 to 6, morepreferably 1 to 3, carbons, halide, alkoxyalkyl, haloalkyl, S or O, orthe like; or

(ii) any two of Z¹-Z⁵ together with the atoms to which each is attachedform a carbon ring or heterocycle fused to the phenyl group. It ispreferable that at least three or four of Z¹-Z⁵ is hydrogen, andpreferably the hydrogens are in the meta positions and ortho positions.Preferred positions for Z¹-Z⁵, when not hydrogen, are the para positionand/or ortho position.

In particular, R¹¹ contains up to about 30 carbon atoms, preferably 1 to10, more preferably 1 to 6 and is selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁵ and S(O)_(n)R¹⁵ in whichn is 0-2; R¹⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl;R¹¹ and R¹⁵ are unsubstituted or are substituted with one or moresubstituents each selected independently from Z, which is hydrogen,halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ in which n is 0-2, NHOH,NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶ and CONR¹²R¹⁶; R¹⁶ is hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl or cycloalkynyl; R¹², which is selectedindependently from R¹¹ and Z, is selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R¹⁷ and S(O)_(n)R¹⁷ in which n is 0-2;and R¹⁷ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; each of R¹¹, R¹², R¹⁵ and R¹⁶ may be further substitutedwith any of hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl,alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, OH and CN.

In preferred embodiments herein, R³ or R⁶ or R⁷ is phenyl. In morepreferred embodiments, R³ is phenyl, and Z²-Z⁵ are hydrogen or loweralkyl, preferably C₁₋₃ alkyl, and Z¹ is in the ortho, or para position,and is preferably lower alkyl, lower alkoxy, halo-lower alkyl or halide.

Compounds in which Ar² is a tricyclic carbocycle or heterocycle are alsoprovided. In particular, preferred among these compounds are compoundsof formula:

in which X is S, O, NR¹⁴ in which R¹⁴ like R¹¹, but selectedindependently from R¹¹, is aryl, hydrogen, or lower alkyl, preferably, asubstituted or unsubstituted aryl, particularly phenyl, preferablyunsubstituted or substituted with lower alkyl or halogen hydrogen orlower alkyl, in which the alkyl groups contain from 1-6 carbons,preferably 1-3 carbons, and are straight, branched or cyclic chains.

In the above compounds, the alkyl, alkynyl and alkenyl portions of eachlisted substituent are straight or branched chains or are cyclic, andpreferably have from about 1 up to about 10 carbons; in more preferredembodiments they have from 1-6 carbons, and they can have fewer than 6carbons. The aryl, carbocyclic, aromatic rings and heterocyclic groupscan have from 3 to 16, generally, 3-7, more often 5-7 members in therings, and may be single or fused rings. The ring size and carbon chainlength are selected up to a size such that the resulting molecule bindsto retains activity as an endothelin antagonist or agonist, such thatthe resulting compound inhibits binding by 50%, compared to binding inthe absence of the sulfonamide, of an endothelin peptide to anendothelin receptor at a concentration of less than about 100 μM.

Of particular interest herein are compounds that inhibit binding ofendothelin to ET_(B) receptors at lower concentrations, preferably atleast 2-fold, more preferably 3-fold, and most preferably at least 5- to10-fold lower than they inhibit binding to ET_(A) receptors.

Preferred compounds are ET_(B) receptor selective or bind to ET_(B)receptors with an IC₅₀ of less than about 1 μM.

Preferred compounds also include compounds that are ET_(B) receptorselective or that competitively inhibit binding of endothelin-1 toET_(B) receptors at IC₅₀ concentrations of 1 μM (if measured at 4° C.;or 5-10 μM, if measured at 24° C.). In preferred compounds, generally R²is selected from among alkyl, lower alkenyl, lower alkynyl, lowerhaloalkyl, halide or H; and R¹ is halide or lower alkyl, and inpreferred embodiments, R¹ is bromide or chloride.

Of the compounds described herein, those that inhibit or increase anendothelin-mediated activity by about 50% at concentrations of less thanabout 10 μM are preferred. More preferred are those that inhibit orincrease an endothelin-mediated activity by about 50% at concentrationsof less than about 1 μM, more preferably less than about 0.1 μM, evenmore preferably less than about 0.01 μM, and most preferably less thanabout 0.005 μM. The preferred IC₅₀ concentrations are set forth withreference to the in vitro assays exemplified herein. It is understoodthat these IC₅₀ concentrations vary from assay to assay. For example, itis noted that, as described below, the IC₅₀ concentration determined inthe in vitro assays is a non-linear function of incubation temperature.The preferred values recited herein refer to the assays that areperformed at 4° C. When the assays are performed at 24° C., somewhathigher (see, Table 1) IC₅₀ concentrations are observed. Accordingly,when the assay is performed at 24° C., the preferred IC₅₀ concentrationsare about 10-fold higher.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein or pharmaceutically acceptablesalts or acids thereof that deliver amounts effective for the treatmentof bronchoconstrictive disorders, and other conditions that are in somemanner mediated by an endothelin peptide or that involvebronchoconstriction or whose symptoms can be ameliorated byadministration of an ET_(B)-specific endothelin antagonist or agonist,are also provided. Particularly preferred compositions are those thatdeliver amounts effective for the treatment of hypertension or renalfailure. The effective amounts and concentrations are effective forameliorating any of the symptoms of any of the disorders.

Methods for inhibiting binding of an endothelin peptide to an endothelinreceptor are provided. These methods are practiced by contacting thereceptor with one or more of the compounds provided hereinsimultaneously, prior to, or subsequent to contacting the receptor withan endothelin peptide.

Methods for treatment of endothelin-mediated disorders, including butnot limited to, asthma, conditions that are in some manner mediated byan endothelin peptide that binds to ET_(B) receptors, or for treatmentof disorder that involves bronchoconstriction or that are ameliorated byadministration of an ET_(B) receptor endothelin antagonist or agonistare provided.

In particular, methods of treating endothelin-mediated disorders byadministering effective amounts of the sulfonamides, prodrugs or othersuitable derivatives of the sulfonamides are provided. In particular,methods for treating endothelin-mediated disorders, includingrespiratory diseases and inflammatory diseases, including asthma,bronchio-constriction, and other diseases in which ET_(B) receptorendothelin mediated physiological responses are implicated, byadministering effective amounts of one or more of the compounds providedherein in pharmaceutically acceptable carriers are provided. Preferredmethods of treatment are methods for treatment of hypertension and renalfailure.

More preferred methods of treatment are those in which the compositionscontain at least one compound that inhibits the interaction of anendothelin with ET_(B) receptors at an IC₅₀ of less than about 10 μM,and preferably less than about 5 μM, more preferably less than about 1μM, even more preferably less than 0.1 μM, and most preferably less than0.05 μM Other preferred methods are those in which the compositionscontain one or more compounds that is (are) ET_(B) selective. Methods inwhich the compounds are ET_(B) selective are for treatment of disorders,such as asthma, that require bronchodilation.

In practicing the methods, effective amounts of compositions containingtherapeutically effective concentrations of the compounds formulated fororal, intravenous, local and topical application for the treatment ofhypertension, cardiovascular diseases, cardiac diseases, includingmyocardial infarction, respiratory diseases, including asthma,inflammatory diseases, ophthalmologic diseases, gastroenteric diseases,renal failure, immunosuppressant-mediated renal vasoconstriction,erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylacticshock, hemorrhagic shock, pulmonary hypertension, and other diseases inwhich endothelin mediated physiological responses are implicated areadministered to an individual exhibiting the symptoms of one or more ofthese disorders. The amounts are effective to ameliorate or eliminateone or more symptoms of the disorders.

Methods for the identification and isolation of endothelin receptorsubtypes, particularly ET_(B) subtypes are also provided. In particular,methods for detecting, distinguishing and isolating endothelin receptorsusing the disclosed compounds are provided. In particular, methods areprovided for detecting, distinguishing and isolating endothelinreceptors using the compounds provided herein.

In addition, methods for identifying compounds that are suitable for usein treating particular diseases based on their preferential affinity fora particular endothelin receptor subtype are also provided.

Articles of manufacture containing packaging material, a compoundprovided herein, which is effective for ameliorating the symptoms of anendothelin-mediated disorder, antagonizing the effects of endothelin orinhibiting binding of an endothelin peptide to an ET_(B) receptor withan IC₅₀ of less than about 10 μM, within the packaging material, and alabel that indicates that the compound or salt thereof is used forantagonizing the effects of endothelin, treating an endothelin-mediateddisorder, or inhibiting the binding of an endothelin peptide to an ETreceptor are provided.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used herein, endothelin (ET) peptides include peptides that havesubstantially the amino acid sequence of endothelin-1, endothelin-2 orendothelin-3 and that act as potent endogenous vasoconstrictor peptides.

As used herein, an endothelin-mediated condition is a condition that iscaused by abnormal endothelin activity or one in which compounds thatinhibit endothelin activity have therapeutic use. Such diseases include,but are not limited to hypertension, cardiovascular disease, asthma,inflammatory diseases, ophthalmologic disease, menstrual disorders,obstetric conditions, gastroenteric disease, renal failure, pulmonaryhypertension, endotoxin shock, anaphylactic shock, or hemorrhagic shock.Endothelin-mediated conditions also include conditions that result fromtherapy with agents, such as erythropoietin and immunosuppressants, thatelevate endothelin levels.

As used herein an effective amount of a compound for treating aparticular disease is an amount that is sufficient to ameliorate, or insome manner reduce the symptoms associated with the disease. Such amountmay be administered as a single dosage or may be administered accordingto a regimen, whereby it is effective. The amount may cure the diseasebut, typically, is administered in order to ameliorate the symptoms ofthe disease. Typically, repeated administration is required to achievethe desired amelioration of symptoms.

As used herein, an endothelin agonist is a compound that potentiates orexhibits a biological activity associated with or possessed by anendothelin peptide.

As used herein, an endothelin antagonist is a compound, such as a drugor an antibody, that inhibits endothelin-stimulated vasoconstriction andcontraction and other endothelin-mediated physiological responses. Theantagonist may act by interfering with the interaction of the endothelinwith an endothelin-specific receptor or by interfering with thephysiological response to or bioactivity of an endothelin isopeptide,such as vasoconstriction. Thus, as used herein, an endothelin antagonistinterferes with endothelin-stimulated vasoconstriction or other responseor interferes with the interaction of an endothelin with anendothelin-specific receptor, such as ET_(A) receptors, as assessed byassays known to those of skill in the art.

The effectiveness of potential agonists and antagonists can be assessedusing methods known to those of skill in the art. For example,endothelin agonist activity can be identified by its ability tostimulate vasoconstriction of isolated rat thoracic aorta or portal veinring segments (Borges et al. (1989) “Tissue selectivity of endothelin”Eur. J. Pharmacol. 165: 223-230). Exemplary assays are set forth in theEXAMPLES. As noted above, the preferred IC₅₀ concentration ranges areset forth with reference to assays in which the test compound isincubated with the ET receptor-bearing cells at 4° C. Data presented forassays in which the incubation step is performed at the less preferred24° C. are identified. It is understood that for purposes of comparison,these concentrations are somewhat higher than the concentrationsdetermined at 4° C.

As used herein, the biological activity or bioactivity of endothelinincludes any activity induced, potentiated or influenced by endothelinin vivo. It also includes the ability to bind to particular receptorsand to induce a functional response, such as vasoconstriction. It may beassessed by in vivo assays or by In vitro assays, such as thoseexemplified herein. The relevant activities include, but are not limitedto, vasoconstriction, vasorelaxation and bronchodilation. For example,ET_(B) receptors appear to be expressed in vascular endothelial cellsand may mediate vasodilation and other such responses; whereas ET_(A)receptors, which are endothelin-1-specific, occur on smooth muscle andare linked to vasoconstriction Any assay known to those of skill in theart to measure or detect such activity may be used to assess suchactivity (see, e.g., Spokes et al. (1989) J. Cardiovasc. Pharmacol.13(Suppl. 5):S191-S192; Spinella et al. (1991) Proc. Natl. Acad. Sci.USA 88: 7443-7446; Cardell et al. (1991) Neurochem. Int. 18:571-574);and the Examples herein).

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as binding of endothelin to tissue receptors, in an assaythat measures such response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

As used herein a sulfonamide that is ET_(A) selective refers tosulfonamides that exhibit an IC₅₀ that is at least about 10-fold lowerwith respect to ET_(A) receptors than ET_(B) receptors.

As used herein, a sulfonamide that is ET_(B) selective refers tosulfonamides that exhibit an IC₅₀ that is at least about 10-fold lowerwith respect to ET_(B) receptors than ET_(A) receptors.

As used herein, pharmaceutically acceptable salts, esters or otherderivatives of the compounds include any salts, esters or derivativesthat may be readily prepared by those of skill in this art using knownmethods for such derivatization and that produce compounds that may beadministered to animals or humans without substantial toxic effects andthat either are pharmaceutically active or are prodrugs. For example,hydroxy groups can be esterified or etherified.

As used herein, treatment means any manner in which the symptoms of aconditions, disorder or disease are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use as contraceptive agents.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular pharmaceutical composition refers to anylessening, whether permanent or temporary, lasting or transient that canbe attributed to or associated with administration of the composition.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis and high performance liquid chromatography (HPLC), usedby those of skill in the art to assess such purity, or sufficiently puresuch that further purification would not detectably alter the physicaland chemical properties, such as enzymatic and biological activities, ofthe substance. Methods for purification of the compounds to producesubstantially chemically pure compounds are known to those of skill inthe art. A substantially chemically pure compound may, however, be amixture of stereoisomers. In such instances, further purification mightincrease the specific activity of the compound.

As used herein, biological activity refers to the in vivo activities ofa compound or physiological responses that result upon in vivoadministration of a compound, composition or other mixture. Biologicalactivity, thus, encompasses therapeutic effects and pharmaceuticalactivity of such compounds, compositions and mixtures.

As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized or otherwise converted to thebiologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, the pharmaceutically active compound ismodified such that the active compound will be regenerated by metabolicprocesses. The prodrug may be designed to alter the metabolic stabilityor the transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound (see, e.g., Nogrady (1985) Medicinal ChemistryA Biochemical Approach, Oxford University Press, New York, pages388-392). For example, succinyl-sulfathiazole is a prodrug of4-amino-N-(2-thiazolyl)benzenesulfonamide (sulfathiazole) that exhibitsaltered transport characteristics.

As used herein, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, pseudohalides are compounds that behave substantiallysimilar to halides. Such compounds can be used in the same manner andtreated in the same manner as halides (X⁻, in which X is a halogen, suchas Cl or Br). Pseudohalides include, but are not limited to cyanide,cyanate, thiocyanate, selenocyanate and azide.

As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer tocarbon chains having less than about 6 carbons. In preferred embodimentsof the compounds provided herein that include alkyl, alkenyl, or alkynylportions include lower alkyl, lower alkenyl, and lower alkynyl portions.

As used herein aryl refers to cyclic groups containing from 3 to 15 or16 carbon atoms, preferably from 5 to 10. Aryl groups include, but arenot limited to groups, such as phenyl, substituted phenyl, naphthyl,substituted naphthyl, in which the substituent is lower alkyl, halogen,or lower alkoxy. Preferred aryl groups are lower aryl groups thatcontain less than 7 carbons in the ring structure.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. are usedas is generally understood by those of skill in this art. For example,as used herein alkyl refers to saturated carbon chains that contain oneor more carbons; the chains may be straight or branched or includecyclic portions or be cyclic. As used herein, alicyclic refers to arylgroups that are cyclic.

As used herein, “haloalkyl” refers to a lower alkyl radical in which oneor more of the hydrogen atoms are replaced by halogen including, but notlimited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl andthe like.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R ishydrogen, alkyl, preferably lower alkyl or aryl, preferably lower aryl.

As used herein “dialkylaminocarbonyl” as used herein refers to —C(O)NR′Rin which R′ and R are independently selected from alkyl or aryl,preferably lower alkyl or lower aryl; “carboxamide” refers to groups offormula NR′COR.

As used herein, “alkoxycarbonyl” as used herein refers to —C(O)OR inwhich R is alkyl, preferably lower alkyl or aryl, preferably lower aryl.

As used herein, “alkoxy” and “thioalkoxy” refer to RO— and RS—, in whichR is alkyl, preferably lower alkyl or aryl, preferably lower aryl.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R isalkyl, preferably lower alkyl or aryl, preferably lower aryl.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl,preferably lower alkyl.

As used herein, cycloalkyl refers to saturated cyclic carbon chains;cycloalkyenyl and cycloalkynyl refer to cyclic carbon chains thatinclude at least one unsaturated triple bond. The cyclic portions of thecarbon chains may include one ring or two or more fused rings.

As used herein, heterocycle or heteroaryl refers to ring structures thatinclude at least one carbon atom and one or more atoms, such as N, S andO. The rings may be single rings or two or more fused rings. Heteroarylis used interchangeably with heterocycle.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem. 11:942).

A. Compounds for Use in Treating Endothelin-Mediated DiseasesIsoxazolylsulfonamides in which Ar² is Phenyl, Biphenyl and FusedCarbocyclic and Heterocyclic Rings

Compounds and methods for treating endothelin-mediated diseases usingthe compounds of formula I are provided. Compounds in which Ar² isselected from phenyl, biphenyl, and aromatic fused rings, includingnaphthyl, anthracenyl, phenanthryl, indenyl, azulenyl, fluorenyl, andphenazinyl and in which Ar¹ is oxazolyl or other heterocycle, such aspyridazinyl, are provided.

In particular, the compounds provided herein have formulae II. When Ar²is phenyl, biphenyl or naphthyl, the compounds are preferably(4-halo-isoxazolyl)sulfonamides or are (4-higheralkyl-isoxazolyl)sulfonmides, in which the alkyl group contains morethan about 8, preferably 9 to 15, more preferably 9 to 13, carbon atoms.

Among the compounds provided herein are those of formulae (III):

in which n is 0 to 10, preferably 0 to 6, more preferably 0 to 3; R³,R⁴, R⁵, R⁶, and R⁷ are selected from (i), (ii), (iii), (iv) or (v) withthe proviso that: (a) when Ar² is phenyl, and R⁴, R⁵, R⁶ and R⁷ arehydrogen, R³ is not NO₂, NH₂ or lower alkyl, particularly CH₃, unless R¹is higher alkyl; and (b) when Ar² is naphthyl, 2-biphenyl or phenyl,other than 3- or 4-biphenyl in which R⁴ and R⁵ are hydrogen or fusedrings (except for naphthyl), R¹ is halide or higher alkyl (C₈-C₁₅preferably C₉-C₁₃):

(i) R³, R⁴, R⁵, R⁶, and R⁷ are each selected independently from among H,NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl,formyl, substituted or unsubstituted amido, substituted or unsubstitutedureido, where the alkyl, alkenyl, alkynyl portions are straight orbranched chains of from about 1 up to about 10 carbons, preferably, 1 toabout 5 or 6 carbons and the aryl portions contain from 3 up to about 10carbons, preferably 6 carbons; or, alternatively,

(ii) R⁴ and R⁷ together are substituted or unsubstituted 1,3-butadienyl,4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl,1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and R³, R⁵ and R⁶are as defined in (i) above; or alternatively,

(iii) R⁷ and R³ together are substituted or unsubstituted1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl,1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups; and n, X, R⁴, R⁵and R⁶ are as defined in (i) above; or

(iv) R³, R⁵, and R⁷ are H or as defined in (i); and R⁴ and R⁶ are eachindependently selected from alkyl, alkoxy, halide, aminoalkyl,dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1to 10, preferably 1 to 6 carbons, and are straight or branched chains;

(v) any two of R³, R⁴, R⁵, R⁶, and R⁷, which are selected as in (i),form fused carbocyclic or heterocyclic rings.

In more preferred embodiments the above compounds in which, R² is H,CH₃, C₂H₅, or CF₃; R¹ is Cl, Br or CH₃; n is 0 or 1; and R³, R⁴, R⁵, R⁶,R⁷, are selected from either (i), (ii), (iii) or (iv) as follows:

(i) R⁵ and R⁶ are H; R⁴ and R⁷ are each independently selected from H,halide, NH₂, CF₃, Ph, CH₃; and R³ is selected from H, NHOH, NH₂, EtNH,(CH₃)₂N, Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃, (CH₃)₃C, C₅H₁₁, CH₃O,n-C₄H₉O, CH₂═CH, Ph—CH═CH, CH≡C, Ph—C≡C, Ph,3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or

(ii) R⁴ and R⁷ together form 1,3-butadienyl, 4-chloro-1,3-butadienyl,4-dimethylamino-1,3-butadienyl or 1-aza-1,3-butadienyl; and R³, R⁵ andR⁶ are defined as in (i) of this embodiment; or

(iii) R⁷ and R³ together form 1,3-butadienyl, 3-chloro-1,3-butadienyl,4-dimethylamino-1,3-butadienyl or 1-aza-1,3-butadienyl; and R⁴, R⁵ andR⁶ are as defined in (i) of this embodiment; or

(iv) R³, R⁵, and R⁷ are H or as defined in (i); and R⁴ and R⁶ are eachindependently selected from alkyl, alkoxy, halide, amino alkyl,alkylaminoalkyl or dialkylaminoalkyl, in which the alkyl and alkoxygroups contain from 1 to 10, preferably 1 to 6 carbons, and are straightor branched chains are provided.

More preferred among the above compounds are those in which Ar² is asubstituted or unsubstituted phenyl, particularly biphenyl, or naphthyl;R¹ is Br, Cl or I; R² is H, CH₃, C₂H₅, CF₃, C₂F₅, n-C₃H₇, cycloC₃H₅, andC₄H₉; and R³, R⁴, R⁵, R⁶ and R⁷ are either (i), (ii), (iii), (iv) or(v):

(i) R⁵, R⁶ and R⁷ are H; n is 0 and R³ is H, NH₂, CH₃ CF₃, halide,C₂H₅NH or Ph, R⁴ is H, CF₃, NH₂, R⁷ is H or CF₃, and R⁵ and R⁶ are H; or

(ii) R³, R⁵ and R⁶ are H; n is 0 and R⁴ and R⁷ together form1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl,or 4-chloro-1,3-butadienyl; or

(iii) R⁴, R⁵ and R⁶ are H; n is 0; and R⁷ and R³ together form1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl,1-aza-1,3-butadienyl; or

(iv) R⁴ is H or NH₂, R⁵ and R⁶ are H; n is 1 and R³ is H, NH₂ andhalide; CH₃, Br, Cl, F, CF₃, NH₂, R⁷ is H, CH₃, Br, Cl, F, NH₂ or CF₃,and R⁵ and R⁶ are H; or

(v) R³, R⁵, and R⁷ are H are as defined in (i); and R⁴ and R⁶ are eachindependently selected from alkyl groups that contain from 1 to 6carbons, and are straight or branched chains, lower alkoxy, and halide.

In more preferred embodiments, the benzenesulfonamides andnaphthalenesulfonamdies are N-(4-halo)-substitutedN-isoxazolylsulfonamides or are 4-higher alkyl-substitutedN-isoxazolylsulfonamides, in which R² is H, CH₃, C₂H₅, C₂F₅ or CF₃; andR³, R⁴, R⁵, R⁶ and R⁷ are either (i) or (ii) as follows:

(i) R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halide,NH₂, CF₃, Ph and CH₃; R³ is selected from H, NHOH, NH₂, C₂H₅NH, (CH₃)₂N,Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃, (CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O,CH₂═CH, Ph—CH═CH, CH≡C, Ph—C≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and3-cyclohexylureido; or

(ii) R³, R⁵ and R⁷ are H; and R⁴ and R⁶ are each an alkyl group thatcontains from 1 to 3 carbons, which are straight or branched chains.

In yet more preferred embodiments, R¹ is most preferably Br or Cl orhigher alkyl (C₉-C₁₃); R² is CH₃, C₂H₅ or CF₃; and R³, R⁴, R⁶ and R⁷ are(i) or (ii) as follows:

(i) R³ is H, NH₂, CH₃ CF₃, halide or C₂H₅NH; R⁴, R⁵ and R⁶ areindependently selected from H, CF₃, halide, particularly Br and Cl, NH₂;and R⁷ is H, CH₃, CH₂CH₃, (CH₃)₂CH, F or CF₃; or

(ii) R³, R⁵ and R⁷ and R⁴ and R⁶ are each an methyl or ethyl.

In all embodiments, R¹ is most preferably Br, except in instances inwhich enhanced ET_(B) affinity, compared to the corresponding compoundin which R₁ is CH₃, is desired, than R¹ is most preferably a higheralkyl (8 to 15 carbons, preferably 9 to 13 carbons).

1. Compounds in Which Ar² is Phenyl and Biphenyl and n is 0

Compounds in which Ar² is phenyl or biphenyl have the following formulae(IV):

in which R³, R⁴, R⁵, R⁶, and R⁷ are selected from (i) or (ii) with theproviso that, (a) when Ar² is phenyl, R³ is not NO₂, NH₂, or loweralkyl, unless R¹ is higher alkyl (C₈-C₁₅, preferably C₉-C₁₃), and (b)when Ar² is naphthyl, 2-biphenyl, or phenyl, other than 3- or 4-biphenyl in which R⁴ and R⁵ is H, dibenzofuryl, dibenzothiophenyl ordibenzopyrrolyl, R¹ is halide or higher alkyl:

(i) R³, R⁴, R⁵, R⁶, and R⁷ are each selected independently from among H,NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl,formyl, substituted or unsubstituted amido, substituted or unsubstitutedureido, where the alkyl, alkenyl, alkynyl portions are straight orbranched chains of from about 1 up to about 10 carbons, preferably, 1 toabout 5 or 6 carbons and the aryl portions contain from 3 up to about 10carbons, preferably 6 carbons; are each independently selected asdescribed above; or, alternatively,

(ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are each independently selectedfrom alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, which areunsubstituted or substituted with alkyl groups, wherein the alkyl andalkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and arestraight or branched chains.

Among the above phenyl and biphenyl compounds, are compounds with thefollowing formulae (V):

in which R³, R⁵ and R⁷ are each independently

(a) hydrogen, except that at least one of R³, R⁵ and R⁷ is other thanhydrogen and any substituent at the 4-position on the phenyl ring is notNH₂, NO₂ or lower alkyl, when the other substituents are hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy,any of which may be substituted with W¹, W² and W³, except that if oneof R³, R⁵ are R⁷ is alkyl at the 4 position, at least one of the othertwo of R³, R⁵ are R⁷ is not hydrogen;

(c) halo;

(d) hydroxyl;

(e) cyano;

(f) nitro, except that if one of R³, R⁵ and R⁷ is 4-NO₂, then at leastone of the other two of R³, R⁵ and R⁷is not hydrogen;

(g) —C(O)H or —C(O)R²⁷;

(h) —CO₂H or —CO₂R²⁷;

(i) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —O—S(O)_(m)OH, or—O—S(O)_(m)OR²⁷;

(j) —W⁴NR²⁸R²⁹, except that, if one of R³, R⁵ and R⁷ is 4-W⁴NR²⁸R²⁹ thenat least one of the other two of R³, R⁵ and R⁷ is not hydrogen; or

(k) —W⁴N(R³²)—W⁵NR³⁰R³¹;

R¹ is halide or is higher alkyl (about 8 carbons up to about 15 carbonsin the chain, preferably C₉-C₁₃), except when the compounds are 3- or4-biphenyls in which the 2-substituent is hydrogen, then R¹ is selected,independently from R² from the substituents set forth for R²;

R² is selected from:

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy,any of which may be substituted with W¹, W² and W³;

(c) hydroxyl;

(d) cyano;

(e) nitro;

(f) —C(O)H or —C(O)R²⁷;

(g) —CO₂H or —CO₂R²⁷;

(h) —SH, —S(O)_(n)R²⁷, —S(O)_(m)OH, —S(O)_(m)OR²⁷, —O—S(O)_(m)—R²⁷,—O—S(O)_(m)OH, or O—S(O)_(m)—OR²⁷;

(i) —W⁴—NR²⁸ R²⁹; or

(j) —W⁴N(R³²)—W⁵—NR³⁰R³¹;

R²⁷ is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R²⁸ is

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

(c) cyano;

(d) hydroxyl;

(e) —C(O)H or —C(O)R²⁷;

(f) —CO₂R²⁷;

(g) —SH, —S(O)_(m)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —O—S(O)_(m)—R²⁷,—O—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷, except when W⁴ is —S(O)_(n)—;

R²⁹ is

(a) hydrogen;

(b) —C(O)H or —C(O)R²⁷, except when W⁴ is —C(O)— and R²⁸ is —C(O)H,—C(O)R²⁷, or —CO₂R²⁷;

(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³; or

R²⁸ and R²⁹ together are alkylene or alkenylene (either of which may besubstituted with W¹, W² and W³), completing a 3- to 8-memberedsaturated, unsaturated or aromatic ring together with the nitrogen atomto which they are attached;

R³⁰ is

(a) hydrogen;

(b) hydroxyl;

(c) —C(O)H or —C(O)R²⁷;

(d) —CO₂R²⁷;

(e) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —O—S(O)_(m)—R²⁷,—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷;

(f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R³¹ is

(a) hydrogen;

(b) —C(O)H or —C(O)R²⁷, except when W⁵ is —C(O)— and R³⁰ is —C(O)H,—C(O)R²⁷, or —CO₂R²⁷; or

(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R³² is

(a) hydrogen;

(b) hydroxyl

(c) —C(O)H, —C(O)R²⁷ or CO₂R²⁷; or

(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

or any two of R³⁰, R³¹ and R³² together are alkylene or alkenylene(either of which may be substituted with W¹, W² and W³), completing a 3-to 8-membered saturated, unsaturated or aromatic ring together with theatoms to which they are attached;

W¹, W² and W³ are each independently

(a) hydrogen;

(b) halo;

(c) hydroxy;

(d) alkyl;

(e) alkenyl;

(f) aralkyl;

(g) alkoxy;

(h) aryloxy;

(i) aralkoxy;

(j) —SH, —S(O)_(n)W⁶, —S(O)_(m)—OH, —S(O)_(m)—OW⁶, —O—S(O)_(m)—W⁶,—O—S(O)_(m)OH, or —O—S(O)_(m)—OW⁶;

(k) oxo;

(l) nitro;

(m) cyano;

(n) —C(O)H or —C(O)W⁶;

(o) —CO₂H or —CO₂W⁶;

(p) —W⁴—NW⁷W⁸;

(q) W⁴—N(W¹¹)—W⁵—W⁶; or

(r) —W⁴—N(W¹¹)—W⁵—NW⁷W⁸;

W⁴ and W⁵ are each independently

(a) a single bond;

(b) —W⁹—S(O)_(n)—W¹⁰—;

(c) —W⁹—C(O)—W¹⁰;

(d) —W⁹—C(S)—W¹⁰—;

(e) —W⁹—O—W¹⁰—;

(f) —W⁹—S—W¹⁰—; or

(g) —W⁹—O—C(O)—W¹⁰—;

W⁶, W⁷ and W⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, oraralkyl, or W⁷ and W⁸ together are alkylene or alkenylene, completing a3- to 8-membered saturated, unsaturated or aromatic ring together withthe nitrogen atom to which they are attached;

W⁹ and W¹⁰ are each independently a single bond, alkylene, alkenylene,or alkynylene;

W¹¹ is

(a) hydrogen;

(b) hydroxyl;

(c) —C(O)H, —C(O)W⁶ or —CO₂W⁶;

(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl; or any two of W⁷ andW⁸ and W¹¹ together are alkylene or alkenylene, completing a 3- to8-membered saturated, unsaturated, or aromatic ring together with theatoms to which they are attached;

m is 1 or 2; and

n is 0, 1, or 2.

Preferred compounds include those in which one of R³, R⁵ or R⁷ is phenylor phenoxy or compounds in which one of R³, R⁵ or R⁷ is hydrogen, one ofthe other two of R³, R⁵ and R⁷ is at the 2 position and is not hydrogen,and the other of R³, R⁵ and R⁷ is at the 5 position. Thus, preferredcompounds are 2-substituted benzenesulfonamides, and 2,5-substitutedbenzenesulfonamides. In addition, in preferred compounds R¹ ispreferably halide or higher alkyl. Preferred substituents are loweralkyl, particular methyl, ethyl, and propyl, halide, amino,dimethylamino, and methoxy.

(a) Benzenesulfonamides (Other Than Biphenylsulfonamides)

Benzene sulfonamides are provided. In these compounds Ar² has theformula (VI):

in which:

R¹ is halide or higher alkyl (greater than 8 carbons); R² selected fromH, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkoxy,haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, aminocarbonyl, haloalkyl, haloaryl,alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted orunsubstituted amido, substituted or unsubstituted ureido, in which thealkyl, alkenyl and alkynyl portions are either straight or branchedchains that contain from 1 up to about 10 carbon atoms, and the arylportions contain from about 4 to about 14 carbons; and

R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or (ii) as follows:

(i) R³, R⁴, R⁵, R⁶, and R⁷ are selected independently from among H,NHOH, NH₂, NO₂, pseudohalide, including N₃, halide, alkenyl, alkynyl,aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl,alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynylportions are straight or branched chains of from about 1 up to about 10carbons, preferably, 1 to about 5 or 6 carbons, are unsubstituted orsubstituted with groups set forth for Z, above, and the aryl portionscontain from 3 up to about 10 carbons, preferably 3 to 6 carbons, and,also are unsubstituted or substituted with groups, independentlyselected from Z, with the proviso that, if R⁴, R⁵, R⁶, and R⁷ are allhydrogen, then R³ is not NO₂, NH₂ or lower alkyl; or

(ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are each independently selectedfrom alkyl, alkoxy, halide, aminoalkyl, dialkylamino, dialkylaminoalkyl,which are unsubstituted or substituted with alkyl groups, and in whichthe alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6carbons, and are straight or branched chains.

Compounds in which at least one of R³-R⁷ is phenyl are discussed belowwith the biphenyl compounds.

In certain preferred embodiments: R¹ is halide or a higher alkylselected from C₉H₁₉ to C₁₃H₂₇; R² is selected independently from alkyl,lower alkenyl, lower alkynyl, lower haloalkyl and H; and R³, R⁴, R⁵, R⁶,and R⁷ are either (i) or (ii) as follows:

(i) R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, loweralkyl, NH₂, NO₂, halide, pseudohalide; R³ is selected from H, NHOH,halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy,alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl,aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl,haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl,substituted or unsubstituted amido, substituted or unsubstituted ureido,where the alkyl, alkenyl, alkynyl portions are straight or branchedchains of from 1 up to 5 or 6 carbons and the aryl portions contain from4 to 14 carbons; or

(ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are each independently selectedfrom alkyl, alkoxy, halide, aminoalkyl, and dialkylaminoalkyl, which areunsubstituted or substituted with alkyl groups, and in which the alkyland alkoxy groups contain 1 to 6 carbons, and are straight or branchedchains.

In more preferred embodiments, R¹ is Cl or Br, or if greater ET_(B)activity is preferred a higher alkyl (C₉H₁₉ to C₁₃H₂₇; R² is selectedfrom H, CH₃, C₂H₅, CF₃, C₂F₅, n-C₃H₇, cyclo-C₃H₇, nC₁₃H₂₇ and nC₉H₁₉;and R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or (ii) as follows:

(i) R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halide,NH₂, CF₃, Ph and CH₃; R³ is selected from H, NHOH, NH₂, C₂H₅NH, (CH₃)₂N,Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃, (CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O,CH₂═CH, Ph—CH═CH, CH≡C, Ph—C≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and3-cyclohexylureido; or

(ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are each independently selectedfrom alkyl and aminoalkyl in which the alkyl groups have from 1 to 6carbons that may from straight or branched chains.

In yet more preferred embodiments, R¹ is Br, Cl or C₉H₁₉ to C₁₃H₂₇; R²is H, CH₃, C₂H₅, or CF₃; and R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or(ii) as follows:

(i) R³ is H, NH₂, CH₃ CF₃, halide or C₂H₅NH; R⁴, R⁵ and R⁶ areindependently selected from H, CH₃, C₂H₅, (CH₃)₂CH, CF₃, halide,particularly Br and Cl, NH₂; and R⁷ is H, CH₃, CH₂CH₃, (CH₃)₂CH, F orCF₃; or

(ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are each independently selectedfrom alkyl groups in which the alkyl groups have from 1 to 3 carbons andmay form straight or branched chains.

Of the above compounds those with ortho and/or meta substituents orthose that are substituted at positions 2 and 5 on the benzene ring aregenerally more preferred, except when the resulting compound is abiphenyl and ET_(B) affinity is desired, then the correspondingpara-substituted compounds are preferred. Compounds with orthosubstituents are more generally more preferred than the correspondingmeta-substituted compounds. This observation is particularly importantwhen activity with respect to ET_(A) receptors is considered. Inaddition, in preferred compounds R¹ is preferably halide. Preferredsubstituents are lower alkyl, particular methyl, ethyl, and propyl,halide, amino, dimethylamino, and methoxy. Other preferred substituentsmay be deduced from the following Table.

Benzenesulfonamides were synthesized and tested using the exemplifiedassays (see, EXAMPLES) and selected results are set forth in Table 1(the N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamides, which are notincluded in the above formulae, are included for comparison with thecorresponding N-(4-halo-3-methyl-5-isoxazolyl)benzenesulfonamide.

TABLE 1 COMPOUND ET_(A) (μM)* ET_(B) (μM)*N-(4-bromo-5-methyl-3-isoxazolyl)benzenesul- 0.097 ± 0.04   31 ± 5.3fonamide 2-chloro-4-fluoro-N-(5-methyl-3-isoxazoly)ben- — —zenesulfonamide N-(4-bromo-5-tert-butyl-3-isoxazolyl)benzenesul- — —fonamide N-(4-chloro-5-methyl-3-isoxazolyl)benzenesul- — — fonamideN-(4-iodo-5-methyl-3-isoxazolyl)benzenesulfon- — — amide4-nitro-N-(4-bromo-5-methyl-3-isoxazolyl)ben- — — zenesulfonamide5-nitro-N-(4-bromo-5-methyl-3-isoxazolyl)ben- — — zenesulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)benzenesul- 0.055 ± 0.005 19.5 ± 4  fonamide N-(4-bromo-3-phenyl-5-isoxazolyl)benzenesul- — — fonamideN-(4-chloro-3-methyl-5-isoxazolyl)benzenesul- ˜0.11  25.6 fonamideN-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesul- — — fonamide4-iso-propyl-N-(4-bromo-3-methyl-5- 17.3  0.78isoxazolyl)benzenesulfonamide 4-bromo-N-(3,4-dimethyl-5-isoxazolyl)ben-8.9 14.4 zenesulfonamide 4-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)ben-3.0  3.8 zenesulfonamide 4-fluoro-N-(3,4-dimethyl-5-isoxazolyl)ben- 7 ±3 57 ± 13 zenesulfonamide 4-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)ben-1.2 15.3 zenesulfonamide3-nitro-N-(3,4-dimethyl-5-isoxazolyl)benzenesul- 13.7  — fonamide3-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 2.8 40 zenesulfonamide4-iodo-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 6.3 ± 2.5 1.05 ± 0.08zenesulfonamide 4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 1.96 ±1   7.02 ± 2   zenesulfonamideN-(4-bromo-3-ethyl-5-isoxazolyl)benzenesulfon- 0.47 ± 0.3  67.1 ± 6  amide 4-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)-4- 1.44 ± 0.8  4.0 ±0.9 benzenesulfonamide 2,5-dimethyl-N-(4-bromo-3-methyl-5- 0.044 ± 0.03 15.5 ± 3   isoxazolyl)benzenesulfonamide2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)ben-  0.20 40.8zenesulfonamide 3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)ben-  0.2138.3 zenesulfonamide 2,5-dimethyl-N-(3,4-di-methyl-5-isoxazolyl)ben- 9.466.3 zenesulfonamide 2,5-dimethyl-N-(4-chloro-3-methyl-5-  0.19 30.7isoxazolyl)benzenesulfonamide4-acetamido-N-(3,4-dimethyl-5-isoxazolyl)ben- 18.1  — zenesulfonamide4-acetamido-N-(4-bromo-3-methyl-5- 6.4 ± 3.5 ˜26isoxazolyl)benzenesulfonamide4-nitro-N-(3,4-dimethyl-5-isoxazolyl)benzenesul- 100 10 fonamide4-nitro-N-(4-bromo-5-methyl-3-isoxazolyl)ben-  53 ± 1.0 9.4 ± 2  zenesulfonamide 2,4,6-trimethyl-N-(3,4-dimethyl-5- 52 ± 4  —isoxazolyl)benzenesulfonamide 2,4,6-trimethyl-N-(4-bromo-3-methyl-5- 5.9± 0.9 45.5 ± 4.4  isoxazolyl)benzenesulfonamide4-iodo-N-(3,4-dimethyl-5-isoxazolyl)benzenesul- 36 ± 3  6 fonamide4-iodo-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 6.3 ± 2.5 1.05 ± 0.08zenesulfonamide 4-chloro-N-(3,4-dimethyl-5-isoxazolyl)ben- 10.2 ± 1.5 29.2 ± 0.07 zenesulfonamide4-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 1.96 ± 1   7.02 ± 2  zenesulfonamide 2-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- .071 ±.06  37 ± 2  zenesulfonamide3,4-dichloro-N-(3,4-dimethyl-5-isoxazolyl)ben- 3.8 ± 1.5 25 ± 6 zenesulfonamide 3,4-dichloro-N-(4-bromo-3-methyl-5- **0.90 ± 0.2   6.9 ±1.8 isoxazolyl)benzenesulfonamide 0.48 ± 0.07 6.5 ± 0.92,4-dichloro-N-(3,4-dimethyl-5-isoxazolyl)ben- 14 ± 7  104 ± 12 zenesulfonamide 2,4-dichloro-N-(4-bromo-3-methyl-5- 2.6 ± 0.3 24 ± 7 isoxazolyl)benzenesulfonamide2-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.16 ± 0.04 35 ± 6 zenesulfonamide 3-fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.14 ±0.06 24.8 zenesulfonamide 2,5-dimethyl-N-(4-chloro-3-methyl-5- 12.7 ±6.7  12 isoxazolyl)benzenesulfonamide4-nitro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 19 ± 5  6.8 ± 3  zenesulfonamide 4-butoxy-N-(3,4-dimethyl-5-isoxazolyl)ben- 9.2 7.4zenesulfonamide 4-butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 3.0 ± 0.72.0 ± 0.8 zenesulfonamide 3-chloro-2-methyl-N-(4-bromo-3-methyl-5- 0.165± 0.13  22 ± 15 isoxazolyl)benzenesulfonamide2-methyl-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.12 ± 0.01 13 ± 1 zenesulfonamide 3-chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5- 0.31 ± 0.0311.2 ± 0.3  isoxazolyl)benzenesulfonamide2,6-difluoro-N-(4-bromo-3-methyl-5- 0.16 ± 0.1  63 ± 10isoxazolyl)benzenesulfonamide 2,5-difluoro-N-(4-bromo-3-methyl-5- 2.4 ±0.2 26.8 ± 3.7  isoxazolyl)benzenesulfonamide2,3,4-trichloro-N-(4-bromo-3-methyl-5-  2.1 ± 0.01 10.2 ± 2.0 isoxazolyl)benzenesulfonamide 2,3-dichloro-N-(4-bromo-3-methyl-5- 0.19 ±0.04 20.4 ± 2.3  isoxazolyl)benzenesulfonamide2,5-dichloro-N-(4-bromo-3-methyl-5- 0.113 ± 0.02 25 ± 3 isoxazolyl)benzenesulfonamide 5-bromo-2-methoxy-N-(4-bromo-3-methyl-5-0.072 ± 0.03  5.3 ± 0.4 isoxazolyl)benzenesulfonamide2-bromo-5-ethyl-N-(4-chloro-3-methyl-5- 0.057 3.5 ± 0.4isoxazolyl)benzenesulfonamide 2-bromo-5-methyl-N-(4-bromo-3-methyl-5-0.046 ± 0.002 11.5 ± 4   isoxazolyl)benzenesulfonamide2-bromo-5-ethyl-N-(4-bromo-3-methyl-5- 0.029 ± 0.010 5.2 ± 1.1isoxazolyl)benzenesulfonamide 5-bromo-2-ethyl-N-(4-bromo-3-methyl-5-0.0028 ± 0.002  5.2 ± 1.1 isoxazolyl)benzenesulfonamide2,5-diethyl-N-(4-bromo-3-methyl-5- 0.0062 ± 0.003  5.2 ± 0.8isoxazolyl)benzenesulfonamide2,5-diethyl-N-(3,4-dimethyl-5-isoxazolyl)ben- 0.027 ± 0.01  17 ± 7 zenesulfonamide 2-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.040 ±0.02  39 ± 4  zenesulfonamide2-cyano-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.18 ± 0.02 ˜80zenesulfonamide 2,4,5-trichloro-N-(4-bromo-3-methyl-5- 1.2 ± 0.1 23 ± 3 isoxazolyl)benzenesulfonamide 3,4-dimethoxy-N-(4-bromo-3-methyl-5- 0.49± 0.18 24 ± 5  isoxazolyl)benzenesulfonamide4-trifluoromethyl-N-(3,4-dimethyl-5- 129 12.1isoxazolyl)benzenesulfonamide 4-trifluormethyl-N-(4-bromo-3-methyl-5- 22 ± 3.0 3.0 ± 0.2 isoxazolyl)benzenesulfonamide3-trifluoromethyl-N-(4-bromo-3-methyl-5- 1.5 ± 0.2  21 ± 0.4isoxazolyl)benzenesulfonamide 2,5-dimethoxy-N-(4-bromo-3-methyl-5- 0.19± 0.03  14 ± 0.7 isoxazolyl)benzenesulfonamide5-chloro-2-methoxy-N-(4-bromo-3-methyl-5- 0.94 ± 0.14 10.2 ± 1  isoxazolyl)benzenesulfonamide 3-chloro-2-methyl-N-(3,4-dimethyl-5- 10.2± 1.5  29.2 ± 0.7  isoxazolyl)benzenesulfonamide3-chloro-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.23 ± 0.06 34.7 ± 1.4 zenesulfonamide N-(4-bromo-3-trifluoromethyl-5-isoxazolyl)ben- 0.33 ±0.08 34.7 ± 1.4  zenesulfonamideN-(4-isothiocyanato-3-methyl-5-isoxazolyl)ben- 0.62 ± 0.3  —zenesulfonamide 3-carboxyl-N-(4-bromo-3-methyl-5- 0.18 ± 0.05 7.6 ± 2.7isoxazolyl)benzenesulfonamide 3,5-dichloro-N-(4-bromo-3-methyl-5- 0.062± 0.02  14.2 ± 1.0  isoxazolyl)benzenesulfonamide3-chloro-5-fluoro-N-(4-bromo-3-methyl-5- 0.54 ± 0.1  17.0 ± 0.7 isoxazolyl)benzenesulfonamide3,5-di(trifluoromethyl)-N-(4-bromo-3-methyl-5- 0.57 ± 0.07 17.1 ± 0.6 isoxazolyl)benzenesulfonamide 2,5-difluoro-N-(4-chloro-3-methyl-5- 0.19± 0.05 58 ± 10 isoxazolyl)benzenesulfonamide2-chloro-5-methyl-N-(4-chloro-3-methyl-5- 0.22 ± 0.04 49 ± 2 isoxazolyl)benzenesulfonamide 2,5-dichloro-N-(4-bromo-3-methyl-5- 0.58 ±0.25 17.4 ± 0.8  isoxazolyl)benzenesulfonamide2-chloro-4-fluoro-N-(4-bromo-3-methyl-5- ˜2.0  31 ± 0.3isoxazolyl)benzenesulfonamide 2,5-difluoro-N-(4-bromo-3-methyl-5- 0.16 ±0.1 63 ± 10 isoxazolyl)benzenesulfonamide2-chloro-5-methyl-N-(4-bromo-3-methyl-5- 1.26 ± 0.19 37 ± 1 isoxazolyl)benzenesulfonamide 2-methyl-5-amino-N-(4-bromo-3-methyl-5-0.34 ± 0.01 ˜100 isoxazolyl)benzenesulfonamide2-methyl-5-dimethylamino-N-(4-bromo-3-methyl- 0.21 ± 0.03 44 ± 8 5-isoxazolyl)benzenesulfonamide 3-acetamido-N-(4-bromo-3-methyl-5- 0.35± 0.05 4.0 ± 1   isoxazolyl)benzenesulfonamide3-bromo-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.23 ± 0.06 9.4 ± 1.4zenesulfonamide 2-phenoxy-5-nitro-N-(4-bromo-3-methyl-5- 0.79 ± 0.1419.5 ± 0.1  isoxazolyl)benzenesulfonamide4-ethyl-N-(4-bromo-3-methyl-5-isoxazolyl)ben- 0.34 ± 0.05  083 ± 0.05zenesulfonamide 2,5-dibromo-3,6-difluoro-N-(4-bromo-3-methyl- 0.035 13.3± 1   5-isoxazolyl)benzenesulfonamide2-trifluoromethoxy-N-(4-bromo-3-methyl-5- 0.017 55 ± 7 isoxazolyl)benzenesulfonamide 2-methyl-5-fluoro-N-(4-bromo-3-methyl-5-0.099 78 ± 8  isoxazolyl)benzenesulfonamide2-butyl-5-bromo-N-(4-bromo-3-methyl-5- 0.038 3.6 ± 0.3isoxazolyl)benzenesulfonamide 2-bromo-5-butyl-N-(4-bromo-3-methyl-5-0.85 ± 0.11 5.4 ± 0.3 isoxazolyl)benzenesulfonamide2-methyl-5-bromo-N-(4-bromo-3-methyl-5- 0.24 13 ± 2 isoxazolyl)benzenesulfonamide 2,5-dipropyl-N-(4-bromo-3-methyl-5- 0.19 ±0.3  14.4 ± 1.8  isoxazolyl)benzenesulfonamide2-dimethylamino-5-methyl-N-(4-bromo-3-methyl- 8.1 ± 0.2 0.93 ± 0.255-isoxazolyl)benzenesulfonamide2-methylamino-5-methyl-N-(4-bromo-3-methyl-5- 0.0081 ± 0.0002 0.93 ±0.25 isoxazolyl)benzenesulfonamide2-methylamino-5-methyl-N-(4-chloro-3-methyl-5- 0.0032 ± 0.0001 5.6 ± 0.6isoxazolyl)benzenesulfonamide2-methyl-5-dimethylamino-N-(4-bromo-3-methyl- 0.25 ± 0.01 31 ± 4 5-isoxazolyl)benzenesulfonamide2-ethyl-5-dimethylamino-N-(4-bromo-3-methyl-5- 0.16 23isoxazolyl)benzenesulfonamide 2-methyl-5-azido-N-(4-bromo-3-methyl-5-0.28 ± 0.04 4.2 ± 0.1 isoxazolyl)benzenesulfonamide2,4-diethyl-N-(4-chloro-3-methyl-5- 0.62 ± 0.13 11.5 ± 3.4 isoxazolyl)benzenesulfonamide 2,4-diethyl-N-(4-bromo-3-methyl-5- 0.56 ±0.08 9.3 ± 3   isoxazolyl)benzenesulfonamide2-butyl-5-bromo-N-(4-chloro-3-methyl-5- 0.051 4.4 ± 0.1isoxazolyl)benzenesulfonamide2-bromo-N-(4-chloro-3-methyl-5-isoxazolyl)ben- 0.086 — zenesulfonamide2-bromo-5-butyl-N-(4-chloro-3-methyl-5- 1.1 4.6 ± 0.6isoxazolyl)benzenesulfonamide2-propyl-5-bromo-N-(3,4-dimethyl-5-isoxazoly)- ˜.020 26 ± 4 benzenesulfonamide 2-propyl-5-bromo-N-(4-bromo-3-methyl-5- ˜0.006 6.55 ±0.2  isoxazolyl)benzenesulfonamide2-propyl-5-bromo-N-(4-chloro-3-methyl-5- — 14 ± 4 isoxazolyl)benzenesulfonamide 4-(N′-Cyclohexylureido-N-(3,4-dimethyl-5-3.8 ± 0.3 100 ± 5  isoxazolyl)benzenesulfonamideN-(4-nonyl-3-trifluoromethyl-5-isoxazolyl)ben- 8.7 ± 0.5 9.2 ± 0.7zenesulfonamide N-(4-tridecyl-3-trifluoromethyl-5-isoxazolyl)ben- 13.2 ±2   1.8 ± 0.5 zenesulfonamideN-(4-ethyl-3-trifluoromethyl-5-isoxazolyl)ben- 0.12 ± 0.02 27 ± 3 zenesulfonamide N-(4-hexyl-3-trifluoromethyl-5-isoxazolyl)ben-  11 ± 2.063 ± 9  zenesulfonamide *results generally from 1, 2 or 3 experimentswith the same preparation **Two preparations

(b) Ar² is biphenyl

Compounds of formulae I and 11 in which Ar¹ is N-(5-isoxazolyl) orN-(3-isoxazolyl) in which Ar² is selected from biphenyl or styrylderivatives. These compounds can be represented by the followingformulae (III):

in which n is 0 to 10, preferably 0 to 6, more preferably 0 to 3;

R¹ and R² are either (i), (ii) or (iii) as follows:

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,arylcarbonyl, formyl, substituted or unsubstituted amido, substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionscontain from 1 up to about 14 carbon atoms and are either straight orbranched chains or cyclic, and the aryl portions contain from about 4 toabout 16 carbons, except that R² is not halide or pseudohalide; or,

(ii) R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or,

(iii) R¹ and R² together form 1,3-butadienyl, and

with the proviso that Ar² is not 2-biphenyl or biphenyl in which R⁴and/or R⁵ is other than hydrogen unless R¹ is a halide or higher(C₈-C₁₅, preferably C₉-C₁₃) alkyl;

at least one of R³, R⁴, R⁵, R⁶, and R⁷ is phenyl, and the remaining ofR³, R⁴, R⁵, R⁶ and R⁷ are selected with the proviso that: (a) when oneof R³, R⁶, and R⁷ is phenyl, then R⁴ and R⁵ are hydrogen, unless R¹ ishalide or higher alkyl (C₈-C₁₅, preferably C₉-C₁₃), and (b) when one ofR⁴ or R⁵ is phenyl, then the other is hydrogen, unless R¹ is halide orhigher alkyl (C₈-C₁₅, preferably C₉-C₁₃):

the others of R³, R⁴, R⁵, R⁶, and R⁷ are selected independently fromamong H, NHOH, NH₂, NO₂, pseudohalide, including N₃, halide, alkenyl,alkynyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl,alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynylportions are straight or branched chains of from about 1 up to about 10carbons, preferably, 1 to about 5 or 6 carbons, are unsubstituted orsubstituted with Z, above, and the aryl portions contain from 3 up toabout 10 carbons, preferably 3 to 6 carbons, and, also are unsubstitutedor substituted with groups.

In more preferred embodiments, R¹ is Cl or Br, or if greater ET_(B)activity is preferred a higher alkyl (C₉H₁₉ to C₁₃H₂₇; R² is selectedfrom H, CH₃, C₂H₅, CF₃, C₂F₅, n-C₃H₇, cyclo-C₃H₇, nC₁₃H₂₇ and nC₉H₁₉;and R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or (ii) as follows:

(i) R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halide,NH₂, CF₃, Ph and CH₃; R³ is selected from H, NHOH, NH₂, C₂H₅NH, (CH₃)₂N,Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃, (CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O,CH₂═CH, Ph—CH═CH, CH≡C, Ph—C≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and3-cyclohexylureido; or

(ii) R³, R⁵, and R⁷ are H; and one of R⁴ and R⁶ is phenyl and the otheris selected from alkyl and aminoalkyl in which the alkyl groups havefrom 1 to 6 carbons that may form straight or branched chains.

In yet more preferred embodiments, R¹ is Br, Cl or C₉H₁₉ to C₁₃H₂₇; R²is H, CH₃, C₂H₅, or CF₃; and R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or(ii), with the proviso that at least one of them is substituted orunsubstituted phenyl, as follows:

(i) R³ is H, NH₂, CH₃ CF₃, Ph, halide or C₂H₅NH; R⁴, R⁵ and R⁶ areindependently selected from H, CH₃, C₂H₅, (CH₃)₂CH, CF₃, halide,particularly Br and Cl, Ph and NH₂; and R⁷ is H, CH₃, CH₂CH₃, (CH₃)₂CH,F or CF₃; or

(ii) R³, R⁵, and R⁷ are H or phenyl; and R⁴ and R⁶ are eachindependently selected from alkyl groups in which the alkyl groups havefrom 1 to 3 carbons and may form straight or branched chains.

In yet more preferred embodiments, R¹ is Br, Cl or C₉H₁₉ to C₁₃H₂₇; R²is H, CH₃, C₂H₅, or CF₃; and R³, R⁴, R⁵, R⁶, and R⁷ are, with theproviso that at one of R³, R⁴, R⁵, R⁶, and R⁷ is unsubstituted orsubstituted phenyl, selected as follows:

R³ is Ph, H, NH₂, CH₃ CF₃, halide or C₂H₅NH; R⁴, R⁵ and R⁶ areindependently selected from Ph, H, CH₃, C₂H₅, (CH₃)₂CH, CF₃, halide,particularly Br and Cl, NH₂; and R⁷ is Ph, H, CH₃, CH₂CH₃, (CH₃)₂CH, For CF₃.

For the 3-or 4-biphenyl compounds, in which R⁴ and/or R⁵ is other thanhydrogen, and for the 2-biphenyl compounds, R¹ is preferably bromide orchloride, methyl or ethyl or (C₉-C₁₃)alkyl, and R² is preferably alkyl.In the most active compounds provided herein, as evidenced by in vitrobinding assays, R¹ is bromide or chloride or, in instances in whichET_(B) selectivity is desired, C₉-C₁₃ alkyl. R¹ is preferably halide,lower alkyl, particularly CH₃, or C₉H₁₉—C₁₃H₂₇.

In preferred embodiments, in which the sulfonamides arebiphenylsulfonamides in which R¹ is halide; R² is selected from alkyl,lower alkenyl, lower alkynyl, lower haloalkyl and H; and the others ofR³-R⁷ that are not phenyl are selected from H, lower alkyl, haloalkyland halide. In preferred of these embodiments, R¹ is Cl or Br, and forthe 3-biphenylsulfonamides and, particularly, the4-biphenylsulfonamides, R¹ is also CH₃; R² is selected from H, CH₃,C₂H₅, CF₃, C₂F₅, n-C₃H₇ and cyclo-C₃H₇; and R²⁶ and R¹³ are eachindependently selected from H, halide, NH₂, CF₃ CH₃, CN, CH₃, (CH₃)₃C,C₅H₁₁, CH₃O, n-C₄H₉O and CH₂═CH.

In yet more preferred embodiments, R² is H, CH₃, C₂H₅, or CF₃; R³-R⁷ areindependently selected from H, CH₃, C₂H₅, CF₃, and halide; and X is O.

In another preferred embodiment, the biphenylsulfonamides are 3- or4-biphenylsulfonamides, in which R⁴ and R⁵ are other than hydrogen. Insuch instances R¹ is preferably, halide or methyl or higher (C₉-C₁₃)alkyl. Such compounds have a higher ET_(B) affinity than the2-biphenylsulfonamides. It is also preferred that the substituent at the2-position is hydrogen. R¹ is selected from halide, CH₃, C₂H₅, CF₃,C₂F₅, n-C₃H₇ and cyclo-C₃H₇, preferably halide or CH₃, and R² isselected from H, CH₃, C₂H₅, CF₃, C₂F₅, n-C₃H₇ and cyclo-C₃H₇; and R³-R⁷are each independently selected from H, halide, NH₂, CF₃ CH₃, CN, CH₃,(CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O and CH₂═CH. In more preferred of theseembodiments, R¹ is halide or CH₃, and R² are selected from H, CH₃, C₂H₅,or CF₃; R³-R⁷ are independently selected from H, CH₃, C₂H₅, CF₃, andhalide.

When Ar² is a biphenyl (n=0) in which R⁴ and R⁵ are other than hydrogen,the compounds are (4-halo-isoxazolyl)sulfonamides or are (4-higheralkyl-isoxazolyl)sulfonamides, in which the alkyl group contains morethan about 8, preferably 9 to 15, more preferably 9 to 13, carbon atoms.

In embodiments described in detail herein, preferred compounds includecompounds that are ET_(B) receptor selective or that bind to ET_(B)receptors with an IC₅₀ of less than about 1 μM (when measured in theassays herein at 4° C.). In these compounds, Ar² is 3-biphenyl,4-biphenyl and R¹ is halide or preferably higher alkyl (C₉H₁₉ toC₁₃H₂₇). R² is selected from among alkyl, lower haloalkyl, H; and R¹ ishalide, lower alkyl or lower haloalkyl, or, when Ar² is phenyl ornaphthyl, R¹ is higher alkyl (nine or more carbon atoms, preferably 9 to13 carbon atoms). When R⁴ or R⁵ are other than hydrogen, then Ar¹ is4-haloisoxazolyl or 4-higher (C₈ to C₁₅, preferably C₉H₁₉ to C₁₃H₂₇)alkylisoxzaolyl are preferred.

Among the above phenyl and biphenyl compounds, are compounds with thefollowing formulae (V):

in which R³, R⁵ and R⁷ are each independently selected as follows, withthe proviso that at least one of R³, R⁵ and R⁷ is phenyl or phenoxy:

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy,any of which may be substituted with W¹, W² and W³;

(c) halo;

(d) hydroxyl;

(e) cyano;

(f) nitro;

(g) —C(O)H or —C(O)R²⁷;

(h) —CO₂H or —CO₂R²⁷;

(i) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —S(O)_(m)OH, or—O—S(O)_(m)OR²⁷;

(j) —W⁴NR²⁸R²⁹, except that, if one of R³, R⁵ and R⁷ is 4-W⁴NR²⁸R²⁹ thenat least one of the other two of R³, R⁵ and R⁷ is not hydrogen; or

(k) —W⁴N(R³²)—W⁵N R³⁰R³¹;

R¹ and R² are each independently selected from:

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy,any of which may be substituted with W¹, W² and W³;

(c) hydroxyl;

(d) cyano;

(e) nitro;

(f) —C(O)H or —C(O)R²⁷;

(g) —CO₂H or —CO₂R²⁷;

(h) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)OR²⁷, —O—S(O)_(m)—R²⁷,—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷;

(i) W⁴ NR²⁸R²⁹; or

(j) —W⁴N(R³²)—W⁵—NR³⁰R³¹;

R¹ is selected with the proviso that when Ar² is a 3- or 4-biphenyl inwhich the substituent at the 2-position is other than hydrogen or whenthe compounds are 2-biphenyls, then R¹ is halide or higher allyl (C₈H₁₇to C₁₅H₃₁, preferably C₉H₁₉ to C₁₃H₂₇);

R²⁷ is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R²⁸ is

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

(c) cyano;

(d) hydroxyl;

(e) —C(O)H or —C(O)R²⁷;

(f) —CO₂R²⁷;

(g) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —O—S(O)_(m)—R²⁷,—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷ except when W4 is —S(O)_(n)—;

R²⁹ is

(a) hydrogen;

(b) —C(O)H or —C(O)R²⁷, except when W⁴ is —C(O)— and R²⁸ is —C(O)H,—C(O)R²⁷, or —CO₂R²⁷;

(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³; or

R²⁸ and R²⁹ together are alkylene or alkenylene (either of which may besubstituted with W¹, W² and W³), completing a 3- to 8-memberedsaturated, unsaturated or aromatic ring together with the nitrogen atomto which they are attached;

R³⁰ is

(a) hydrogen;

(b) hydroxyl;

(c) —C(O)H or —C(O)R²⁷;

(d) —CO₂R²⁷;

(e) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —O—S(O)_(m)—R²⁷,—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷;

(f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R³¹ is

(a) hydrogen;

(b) —C(O)H or —C(O)R²⁷, except when W⁵ is —C(O)— and R³⁰ is —C(O)H,—C(O)R²⁷, or —CO₂R²⁷; or

(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R³² is

(a) hydrogen;

(b) hydroxyl

(c) —C(O)H, —C(O)R²⁷ or CO₂R²⁷; or

(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

or any two of R³⁰, R³¹ and R³² together are alkylene or alkenylene(either of which may be substituted with W¹, W² and W³), completing a 3-to 8-membered saturated, unsaturated or aromatic ring together with theatoms to which they are attached; W¹, W² and W³ are each independently

(a) hydrogen;

(b) halo;

(c) hydroxy;

(d) alkyl;

(e) alkenyl;

(f) aralkyl;

(g) alkoxy;

(h) aryloxy;

(i) aralkoxy;

(j) —SH, —S(O)_(n)W⁶, —S(O)_(m)—OH, —S(O)_(m)—OW⁶, —O—S(O)_(m)—W⁶,—O—S(O)_(m)OH, or —O—S(O)_(m)—OW⁶;

(k) oxo;

(l) nitro;

(m) cyano;

(n) —C(O)H or —C(O)W⁶;

(o) —CO₂H or —CO₂W⁶;

(p) —W⁴-NW⁷W⁸;

(q) W⁴—N(W¹¹)—W⁵—W⁶; or

(r) —W⁴—N(W¹¹)—W⁵—NW⁷W⁸;

W⁴ and W⁵ are each independently

(a) a single bond;

(b) —W⁹—S(O)_(n)—W¹⁰;

(c) —W⁹—C(O)—W¹⁰;

(d) —W⁹—C(S)—W¹⁰;

(e) —W⁹—O—W¹⁰;

(f) —W⁹—S—W¹⁰—; or

(g) —W⁹—O—C(O)—W¹⁰—;

W⁶, W⁷ and W⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, oraralkyl, or W⁷ and W⁸ together are alkylene or alkenylene, completing a3- to 8-membered saturated, unsaturated or aromatic ring together withthe nitrogen atom to which they are attached;

W⁹ and W¹⁰ are each independently a single bond, alkylene, alkenylene,or alkynylene;

W¹¹ is

(a) hydrogen;

(b) hydroxyl;

(c) —C(O)H, —C(O)W⁶ or —CO₂W⁶;

(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl;

or any two of W⁷ and W⁸ and W¹¹ together are alkylene or alkenylene,completing a 3- to 8-membered saturated, unsaturated, or aromatic ringtogether with the atoms to which they are attached;

m is 1 or 2; and

n is 0, 1, or 2,

with the proviso that (i) R² is not halide; and (ii) unless R⁵ ishydrogen, R¹ is halide or is higher alkyl (greater than about 8 carbonsup to 15 carbons in the chain, preferably nine to thirteen carbons).

If R⁵ is hydrogen, then R¹ is also preferably selected from lower alkyl,preferably methyl or ethyl, halide or higher alkyl.

Preferred compounds among these include those in which one of R³, R⁵ orR⁷ is phenyl. Preferred substituents on the rings are lower alkyl,particular methyl, ethyl, and propyl, halide, amino, dimethylamino, andmethoxy. In addition, in preferred compounds R¹ is preferably halide orhigher alkyl.

In more preferred compounds, R¹ is Cl or Br, or if greater ET_(B)activity is preferred a higher alkyl (C₉H₁₉ to C₁₃H₂₇; R² is selectedfrom H, CH₃, C₂H₅, CF₃, C₂F₅, n-C₃H₇, cyclo-C₃H₇, nC₁₃H₂₇ and nC₉H₁₉;and R³, R⁵, and R⁷ are each independently selected from H, halide, NH₂,CF₃, Ph and CH₃; R³ is selected from H, NHOH, NH₂, C₂H₅NH, (CH₃)₂N,Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃, (CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O,CH₂═CH, Ph—CH═CH, CH≡C, Ph—C≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and3-cyclohexylureido, with the proviso that at least one of R³, R⁵, and R⁷is a substituted or unsubstituted phenyl. Preferred substituents arelower alkyl, alkoxy(lower)alkyl, halide, and the like. Preferredpositions for the substituents are ortho and/or para.

In yet more preferred embodiments, R¹ is Br, Cl or C₉H₁₉ to C₁₃H₂₇; R²is H, CH₃, C₂H₅, or CF₃; and R³, R⁵ and R⁷, with the proviso that atleast one of R³, R⁵ and R⁷ is phenyl, are selected as follows:

R³ is H, Ph, NH₂, CH₃ CF₃, halide or C₂H₅NH; R⁵ is selected from H, CH₃,C₂H₅, (CH₃)₂CH, CF₃, halide, particularly Br and Cl, NH₂ or Ph; and R⁷is H, Ph, CH₃, CH₂CH₃, (CH₃)₂CH, F or CF₃.

Of any of these compounds described above, those with formulae VI:

in which R⁵ is hydrogen are more preferred. In these compounds R³ and R⁷are each independently selected as follows, with the proviso that one ofR³and R⁷is phenyl or phenoxy, preferably phenyl and the other is:

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy,any of which may be substituted with W¹, W² and W³;

(c) halo;

(d) hydroxyl;

(e) cyano;

(f) nitro;

(g) —C(O)H or —C(O)R²⁷;

(h) —CO₂H or —CO₂R²⁷;

(i) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —O—S(O)_(m)OH, or—O—S(O)_(m)OR²⁷;

(j) —W⁴NR²⁸R²⁹, except that, if one of R³, R⁵ and R⁷ is 4-W⁴NR²⁸R²⁹ thenat least one of the other two of R³, R⁵ and R⁷ is not hydrogen; or

(k) —W⁴N(R³²)—W⁵NR³⁰R³¹;

R¹ and R² are each independently selected from:

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl, or aralkoxy,any of which may be substituted with W¹, W² and W³;

(c) hydroxyl;

(d) cyano;

(e) nitro;

(f) —C(O)H or —C(O)R²⁷;

(g) —CO₂H or —CO₂R²⁷;

(h) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)OR²⁷, —O—S(O)_(m)—R²⁷,—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷;

(i) —W⁴—NR²⁸R²⁹; or

(j) —W⁴N(R³²)—W⁵—NR³⁰R³¹;

R²⁷ is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R²⁸ is

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

(c) cyano;

(d) hydroxyl;

(e) —C(O)H or —C(O)R²⁷;

(f) —CO₂R²⁷;

(g) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —S(O)_(m)—R²⁷,—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷, except when W4 is —S(O)_(n)—;

R²⁹ is

(a) hydrogen;

(b) —C(O)H or —C(O)R²⁷, except when W⁴ iS —C(O)— and R²⁸ is —C(O)H,—C(O)R²⁷, or —CO₂R²⁷;

(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³; or

R²⁸ and R²⁹ together are alkylene or alkenylene (either of which may besubstituted with W¹, W² and W³), completing a 3- to 8-memberedsaturated, unsaturated or aromatic ring together with the nitrogen atomto which they are attached;

R³⁰ is

(a) hydrogen;

(b) hydroxyl;

(c) —C(O)H or —C(O)R²⁷;

(d) —CO₂R²⁷;

(e) —SH, —S(O)_(n)R²⁷, —S(O)_(m)—OH, —S(O)_(m)—OR²⁷, —O—S(O)_(m)-R²⁷,—O—S(O)_(m)OH, or —O—S(O)_(m)—OR²⁷;

(f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R³¹ is

(a) hydrogen;

(b) —C(O)H or —C(O)R²⁷, except when W⁵ is —C(O)— and R³⁰ is —C(O)H,—C(O)R²⁷, or —CO₂R²⁷; or

(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

R³² is

(a) hydrogen;

(b) hydroxyl

(c) —C(O)H, —C(O)R²⁷ or CO₂R²⁷; or

(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl, any of which may besubstituted with W¹, W² and W³;

or any two of R³⁰, R³¹ and R³² together are alkylene or alkenylene(either of which may be substituted with W¹, W² and W³), completing a 3-to 8-membered saturated, unsaturated or aromatic ring together with theatoms to which they are attached; W¹, W² and W³ are each independently

(a) hydrogen;

(b) halo;

(c) hydroxy;

(d) alkyl;

(e) alkenyl;

(f) aralkyl;

(g) alkoxy;

(h) aryloxy;

(i) aralkoxy;

(j) —SH, —S(O)_(n)W⁶, —S(O)_(m)—OH, —S(O)_(m)—OW⁶, —O—S(O)_(m)—W⁶,—O—S(O)_(m)OH, or —O—S(O)_(m)—OW⁶;

(k) oxo;

(l) nitro;

(m) cyano;

(n) —C(O)H or —C(O)W⁶;

(o) —CO₂H or —CO₂W⁶;

(p) —W⁴—NW⁷W⁸;

(q) W⁴—N(W¹¹)—W⁵—W⁶; or

(r) —W⁴—N(W¹¹)—W⁵—NW⁷W⁸;

W⁴ and W⁵ are each independently

(a) a single bond;

(b) —W⁹—S(O)_(n)—W¹⁰—;

(c) —W⁹—C(O)—W¹⁰—;

(d) —W⁹—C(S)—W¹⁰—;

(e) —W⁹—O—W¹⁰—;

(f) —W⁹—S—W¹⁰—; or

(g) —W⁹—O—C(O)—W¹⁰;

W⁶, W⁷ and W⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, oraralkyl, or W⁷ and W⁸ together are alkylene or alkenylene, completing a3- to 8-membered saturated, unsaturated or aromatic ring together withthe nitrogen atom to which they are attached;

W⁹ and W¹⁰ are each independently a single bond, alkylene, alkenylene,or alkynylene;

W¹¹ is

(a) hydrogen;

(b) hydroxyl;

(c) —C(O)H, —C(O)W⁶ or —CO₂W⁶;

(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl;

or any two of W⁷ and W⁸ and W¹¹ together are alkylene or alkenylene,completing a 3- to 8-membered saturated, unsaturated, or aromatic ringtogether with the atoms to which they are attached;

m is 1 or 2; and

n is 0, 1, or 2.

In the more preferred of these compounds, R¹, R², R³ and R⁷ are selectedas in the more preferred compounds of formulae (V). Most preferred arecompounds in which Ar² is 4-biphenyl.

The biphenyl compounds provided herein are generally ET_(B) active orET_(B) selective (see, e.g., Table 2); i.e. the compounds providedherein inhibit binding of endothelin to ET_(B) receptors atconcentrations about 10- to about 30-fold less than they inhibit bindingof endothelin to ET_(A) receptors. In particular the4-biphenylsulfonamides are ET_(B) selective.

In general in all embodiments herein, 4-haloisoxazolyl sulfonamidesexhibit substantially enhanced activity with respect to at least one ofthe ET receptors (about two-fold to twenty-fold greater activity), asassessed by assays, such as those provided herein, that measure bindingto ET_(A) and/or ET_(B) receptors, compared to correspondingsulfonamides in which the substituent at the 4 position in theisoxazolyl is other than halo, such as alkyl. For example: the IC₅₀ ofN-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfonamide for ET_(A) receptorsis about 0.008 μM, whereas, the IC₅₀ ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide is about 0.0016μM (see, Table below); and (3) the IC₅₀ ofN-(3,4-dimethyl-5-isoxazolyl)-3-biphenylsulfonamide for ET_(B) receptorsis about 3.48 μM; whereas, the IC₅₀ ofN-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide for ET_(B)receptors is about 0.76 μM and the IC₅₀ ofN-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide for ET_(B)receptors is about 0.793 μM (see, Table below).

Exemplary biphenyl sulfonamides are the following and those set forth inTable 2, and include, but are not limited to:N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide,N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide,N-(4-chloro-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide,N-(3-methyl-5-isoxazolyl)-4′-methylphenyl-4-biphenylsulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-4′-methylphenyl-4-biphenylsulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-4′-methylphenyl-4-biphenylsulfonamide,(3-methyl-5-isoxazolyl)-4′-trifluorophenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazolyl)-4′-trifluorophenyl-4-biphenylsulfonamide,(3-methyl-5-isoxazolyl)-4′-methyoxyphenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazoly-)-4′-methoxyphenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazolyl)-3′-methoxyphenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazolyl)-2′-methoxyphenyl-4-biphenylsulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3′,4′-methylenedioxyphenyl-4-biphenylsulfonamideand(4-bromo-3-methyl-5-isoxazolyl)-3′-methylphenyl-4-biphenylsulfonamide.Corresponding 4-chloro and 4-fluoro isoxazolyl compounds are alsoencompassed herein.

Exemplary biphenyl compounds were tested using the exemplified assays(see, EXAMPLES) and the results, which are intended to be exemplary andnot limiting, are as set forth in the following table (Table 2):

TABLE 2 COMPOUND ET_(A) (μM)* ET_(B) (μM)*N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsul- 3.3 ˜0.17 fonamide 49†1.23† N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsul- 6.4 ± 2   0.29 ±0.02 fonamide 49† 1.78†N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsul- 4.93 ± 3   0.29 ± 0.1 fonamide N-(3,4-dimethyl-5-isoxazolyl)-4- 9.9 ± 1.4 0.77 ± 0.32biphenylsufonamide 6.3† 0.15†N-(4-chloro-5-methyl-3-isoxazolyl)-4-biphenylsul- 3.7 0.23 ± 0.01fonamide 18.6† 1.29† N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4- 19.01.7 biphenylsulfonamide — 5.62†N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4- 34.0 ± 9??  0.99 ±0.2?? biphenylsulfonamide 33.0† 0.95†N-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfon- 0.0083 ± 0.0014 12.8amide N-(4-chloro-3-methyl-5-isoxazolyl)-2-biphenylsul- 0.00123** ˜14**fonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-biphenylsulfon- 0.00123**˜14** amide N-(3,4-dimethyl-5-isoxazolyl)-3-biphenylsulfon- >0.03**3.48** amide N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsul- ˜0.03**0.76** fonamideN-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsul- >0.03** 0.793**fonamide N-(3-methyl-5-isoxazolyl)-4′-methylphenyl-4- >100 3.2 ± 0.36biphenylsulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4′- 14.53 ± 9.6 0.046 ± 0.044 methylphenyl-4-biphenylsulfonamide 22.17 ± 3.77†  0.168 ±0.0032† N-(4-chloro-3-methyl-5-isoxazolyl)-4′- — —methylphenyl-4-biphenylsulfonamide(3-methyl-5-isoxazolyl)-4′-trifluorophenyl-4- 72 5.6 ± 1.0biphenylsulfonamide (4-bromo-3-methyl-5-isoxazolyl)-4′-trifluorophenyl-5.4 ± 0.3 0.083 ± 0.02 4-biphenylsulfonamide  25.9 ± 13.7†  0.71 ± 0.43†(3-methyl-5-isoxazolyl)-4′-methyoxyphenyl-4- — 78 biphenylsulfonamide(4-bromo-3-methyl-5-isoxazolyl)-4′- 14.7 ± 5.6  1.15 ± 0.44methoxyphenyl-4-biphenylsulfonamide 121.5 ± 2.12†  3.94 ± 0.89†(4-bromo-3-methyl-5-isoxazolyl)-3′- 4.97 ± 3.4  0.66 ± 0.25methoxyphenyl-4-biphenylsulfonamide 162.6 ± 7.14†  2.08 ± 0.23†(4-bromo-3-methyl-5-isoxazolyl)-2′- 3.3 ± 3.5 0.41 ± 0.14methoxyphenyl-4-biphenylsulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3′,4′-  38.2 ± 4.95†  3.0 ± 0.78†methylenedioxyphenyl-4-biphenylsulfonamide(4-bromo-3-methyl-5-isoxazolyl)-3′-methylphenyl- — —4-biphenylsulfonamide *results generally from 1, 2 or 3 experiments withthe same preparation **preliminary results

The preparation of the above and other compounds that possess therequisite activities are set forth in the Examples.

2. Ar² is Fused Ring Carbocycle or Heterocycle, Including Dibenzofuryl,Dibenzothiophenyl, Dibenzopyrrolyl and Phenanthrene

Compounds in Ar² is a carbocycle containing two or more fused rings or aheterocycle with one heteroatom and two or more fused rings areprovided. The heteroatom is O, S or N (NR¹⁴) and Ar² is selected fromamong, but not limited to, quinolyl, isoquinolyl, dibenzofuryl,dibenzothiophenyl, and dibenzopyrrolyl compounds and other such groups.The fused rings may be substituted with one or more substituentsselected from among substituents set forth for R³-R⁷ or Z above, at anyposition. The sulfonamide portion of the compounds may be linked at anyposition on the rings.

In certain embodiments Ar² is dibenzofuryl, dibenzothiophenyl,dibenzopyrrolyl or phenanthrene or other tricyclic fused ring, and hasthe following formula (V):

in which: R¹ and R² are selected as described above for the thiophenyl,furyl and pyrrolyl compounds; X is —CH═CH—, O, S, NR¹⁴, in which R¹⁴ isselected independently from the groups set forth above for R¹¹(compounds in which X is —CH═CH— are phenanthrenesulfonamides); and

Ar² is unsubstituted or substituted with one or more substituentsselected from R¹³ and R²⁶, which are each independently (i) or (ii):

(i) R²⁶ and R¹³ are independently selected from H, OH, OHNH, NH₂, NO₂,halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio, haloalkoxy,haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl,substituted or unsubstituted amido, substituted or unsubstituted ureido,in which the alkyl, alkenyl and alkynyl portions contain from 1 up toabout 14 carbon atoms, preferably from 1 to 6 atoms, and are eitherstraight or branched chains or cyclic, and the aryl portions containfrom about 4 to about 16 carbons, preferably 4 to 10 carbons; or

(ii) R²⁶ and R¹³ together are —CH₂—, —CH═CH₂—, O, S, NR¹¹ in which R¹¹is as defined above, and is preferably, H or alkyl, particularly loweralkyl. It is understood that in either (i) or (ii) each ring of Ar² maybe unsubstituted or substituted with more than one substituent, each ofwhich is selected independently from the selections set forth in (i) forR²⁶ and R¹³.

These compounds, thus, include fused tricyclic-substituted sulfonamides,dibenzothiophenesulfonamides, dibenzofuransulfonamides,dibenzopyrrolesulfonamides (carbazolesulfonamides) andphenanthrenesulfonamides.

In more preferred embodiments, R¹ is halide or methyl; R² is selectedfrom lower alkyl, lower alkenyl, lower alkynyl and lower haloalkyl; R²⁶and R¹³ are independently selected from H, lower alkyl, haloalkyl andhalide. In more preferred embodiments R¹ is Cl, Br or CH₃; R² isselected from H, CH₃, C₂H₅, CF₃, n-C₃H₇, cyclo-C₃H₇ and C₄H₉; and R²⁶and R¹³ are each independently selected from H, halide, NH₂, CF₃, CH₃,CN, CH₃, (CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O and CH₂═CH. In yet more preferredembodiments, R² is H, CH₃, C₂H₅, or CF₃; R²⁶ and R¹³ are independentlyselected from H, CH₃, C₂H₅, CF₃, and halide; and X is O.

Exemplary compounds include those set forth in Table 3:

TABLE 3 COMPOUND ET_(A) (μM)* ET_(B) (μM)*N-(4-bromo-3-methyl-5-isoxazolyl)dibenzofuran-4-sul- **0.39 **10fonamide N-(3,4-dimethyl-5-isoxazolyl)-2-dibenzofuransulfon- — — amideN-(3,4-Dimethyl-5-isoxazolyl)-3-dibenzofuransulfon- 6.1 ± 1.2 0.81 ±0.13 amide N-(4-bromo-3-methyl-5-isoxazolyl)-3-dibenzofuransul- 1.05 ±0.05 0.23 ± 0.05 fonamideN-(3,4-dimethyl-5-isoxazolyl)dibenzothiophene-4-sul- 0.37 ± 0.06 1.8 ±0.4 fonamide N-(4-bromo-3-methyl-5-isoxazolyl)dibenzothiophene-4- 0.115± 0.02  0.47 ± 0.13 sulfonamide *results based on 1 to 4 experiments

B. Preparation of the Compounds

The preparation of the above compounds is described in detail in theexamples. Any such compound or similar compound may be synthesizedaccording to a method discussed in general below and by only minormodification of the methods set forth in the Examples by selectingappropriate starting materials as exemplified.

In general, most of the syntheses involve the condensation of a sulfonylchloride with an aminoisoxazole in dry pyridine or in tetrahydrofuran(THF) and sodium hydride. The sulfonylchlorides and aminoisoxazoleseither can be obtained commercially or synthesized according to methodsdescribed in the Examples or using other methods available to those ofskill in this art (see, e.g., U.S. Pat. Nos. 4,659,369, 4,861,366 and4,753,672).

The compounds may be prepared by reacting an appropriate sulfonylchloride with 5-aminoisoxazoles substituted at the 3 and 4 positions (or4 and 5 positions in the case of 3-isoxazolyl derivatives), such as5-amino-4-bromo-3-methylisoxazole, in tetrahydrofuran (THF) solutioncontaining a base, such as sodium hydride. Following the reaction, theTHF is removed under reduced pressure, the residue dissolved in water,acidified and extracted with methylene chloride. The organic layer iswashed and then dried over anhydrous magnesium sulfate, the solvents areevaporated and the residue is purified by recrystallization usinghexanes/ethyl acetate to yield pure product. TheN-(4-haloisoxazolyl)sulfonamides can be prepared by condensation ofamino-4-haloisoxazole with a sulfonyl chloride in THF with sodiumhydride as a base.

In some cases, the bis-sulfonyl compound is obtained as the major orexclusive product. The bis-sulfonated products can be readily hydrolyzedto the sulfonamide using aqueous sodium hydroxide and a suitableco-solvent, such as methanol or tetrahydrofuran, generally at roomtemperature.

Alternatively, the sulfonamides can be prepared from the correspondingsulfonyl chloride and the aminoisoxazole in pyridine with or without acatalytic amount of 4-dimethylaminopyridine (DMAP). In some cases, thebis-sulfonyl compound is obtained as the major or exclusive product. Thebis-sulfonated products can be readily hydrolyzed to the sulfonamideusing aqueous sodium hydroxide and a suitable co-solvent, such asmethanol or tetrahydrofuran, generally at room temperature.

The N-(alkylisoxazolyl)sulfonamides can be prepared by condensing anaminoisoxazole with a sulfonyl chloride in dry pyridine with or withoutthe catalyst 4-(dimethylamino)pyridine. TheN-(3,4-dimethyl-5-isoxazolyl)sulfonamides andN-(4,5-dimethyl-5-isoxazolyl)sulfonamides can be prepared from thecorresponding aminodimethylisoxazole, such as5-amino-3,4-dimethylisoxazole. TheN-(3,4-dimethyl-5-isoxazolylsulfonamides and theN-(4,5-dimethyl-3-isoxazolylsulfonamdies can be prepared from thecorresponding aminodimethylisoxaole, such as5-amino-3,4-dimethylisoxazole.

Exemplary preparations of numerous compounds herein are set forth in theExamples. For example compounds, such asN-(3,4-dimethyl-5-isoxazolyl)biphenylsulfonamide (EXAMPLE 1), can beprepared from 4-biphenylsulfonyl chloride and an amino-substitutedisoxazole, such as 5-amino-3,4-dimethylisoxazole, in dry pyridine (2.0ml). Following the reaction, the pyridine is removed under reducedpressure and the residue is partitioned between water and ethyl acetate.The organic layer is washed and then dried over anhydrous magnesiumsulfate, the solvents are evaporated and the residue is purified bycolumn chromatography over silica gel (e.g., 1% methanol in chloroformas eluent) to yielded a solid. Further purification is achieved byrecrystallization from ethyl acetate/hexanes, to yield the pure product.Alternatively, the sulfonamides can be prepared from the correspondingaminoisoxazole in tetrahydrofuran solution containing sodium hydride.

The compounds, such asN-(3,4-dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide (see, em,EXAMPLE 3) can be prepared by reacting 5-amino-3,4-dimethylisoxazole and2-dibenzofuransulfonyl chloride in dry pyridine. Following the reaction,the pyridine is removed under reduced pressure and the residue ispartitioned between water and ethyl acetate. The organic layer is washedand then dried over anhydrous magnesium sulfate, the solvents areevaporated and the residue is purified by column chromatography oversilica gel (e.g., 1% methanol in chloroform as eluent) to yield a solid.Further purification is achieved by recrystallization from ethylacetate/hexanes or column chromatography, to yield the pure product.

Prodrugs and other derivatives of the compounds suitable foradministration to humans may also be designed and prepared by methodsknown to those of skill in the art (see, e.g., Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392.

Compounds listed and described have been synthesized and tested foractivity in in vitro assays and, in some cases, in vivo animal models.Nuclear magnetic resonance spectroscopic (NMR), mass spectrometric,infrared spectroscopic and high performance liquid chromatographicanalyses indicated that the synthesized compounds have structuresconsistent with those expected for such compounds and are generally atleast about 98% pure. All of the compounds exemplified or describedherein exhibited activity as endothelin antagonists.

C. Evaluation of the Bioactivity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possess anybiological activities of an endothelin peptide or the ability tointerfere with or inhibit endothelin peptides. Compounds that exhibit invitro activities, such as the ability to bind to endothelin receptors orto compete with one or more of the endothelin peptides for binding toendothelin receptors can be used in the methods for isolation ofendothelin receptors and the methods for distinguishing thespecificities of endothelin receptors, and are candidates for use in themethods of treating endothelin-mediated disorders.

Thus, other preferred compounds of formulas I and II, in addition tothose of specifically identified herein, that are endothelin antagonistsor agonists may be identified using such screening assays.

1. Identifying Compounds that Modulate the Activity of an EndothelinPeptide

The compounds are tested for the ability to modulate the activity ofendothelin-1. Numerous assays are known to those of skill in the art forevaluating the ability of compounds to modulate the activity ofendothelin (see, e.g.., U.S. Pat. No. 5,114,918 to Ishikawa et al.; EPA1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD. (Oct. 7, 1991); Borges etal. (1989) Eur. J. Pharm. 165: 223-230; Filep et al. (1991) Biochem.Biophys. Res. Commun. 177: 171-176). In vitro studies may becorroborated with in vivo studies (see, e.g., U.S. Pat. No. 5,114,918 toIshikawa et al.; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD. (Oct.7, 1991)) and pharmaceutical activity thereby evaluated. Such assays aredescribed in the Examples herein and include the ability to compete forbinding to ET_(A) and ET_(B) receptors present on membranes isolatedfrom cell lines that have been genetically engineered to express eitherET_(A) or ET_(B) receptors on their cell surfaces.

The properties of a potential antagonist may be assessed as a functionof its ability to inhibit an endothelin induced activity in vitro usinga particular tissue, such as rat portal vein and aorta as well as ratuterus, trachea and vas deferens (see e.g., Borges, R., Von Grafenstein,H. and Knight, D. E., Tissue selectivity of endothelin, Eur. J.Pharmacol 165:223-230, (1989)). The ability to act as an endothelinantagonist in vivo can be tested in hypertensive rats, ddy mice or otherrecognized animal models (see, Kaltenbronn et al. (1990) J. Med. Chem.33:838-845, see, also, U.S. Pat. No. 5,114,918 to Ishikawa et al; and EPA1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (Oct. 7, 1991); see, alsoBolger et al. (1983) J. Pharmacol. Exp. Ther. 225 291-309). Using theresults of such animal studies, pharmaceutical effectiveness may beevaluated and pharmaceutically effective dosages determined. A potentialagonist may also be evaluated using in vitro and in vivo assays known tothose of skill in the art.

Endothelin activity can be identified by the ability of a test compoundto stimulate constriction of isolated rat thoracic aorta (Borges et al.(1989) “Tissue selectivity of endothelin” Eur. J. Pharmacol. 165:223-230). To perform the assay, the endothelium is abraded and ringsegments mounted under tension in a tissue bath and treated withendothelin in the presence of the test compound. Changes in endothelininduced tension are recorded. Dose response curves may be generated andused to provide information regarding the relative inhibitory potency ofthe test compound. Other tissues, including heart, skeletal muscle,kidney, uterus, trachea and vas deferens, may be used for evaluating theeffects of a particular test compound on tissue contraction.

Endothelin isotype specific antagonists may be identified by the abilityof a test compound to interfere with endothelin binding to differenttissues or cells expressing different endothelin-receptor subtypes, orto interfere with the biological effects of endothelin or an endothelinisotype (Takayanagi et al. (1991) Reg. Pep. 32: 23-37, Panek et al.(1992) Biochem. Biophys. Res. Commun. 183: 566-571). For example, ET_(B)receptors are expressed in vascular endothelial cells, possiblymediating the release of prostacyclin and endothelium-derived relaxingfactor (De Nucci et al. (1988) Proc. Natl. Acad. Sci. USA 85:9797).ET_(A) receptors are not detected in cultured endothelial cells, whichexpress ET_(B) receptors.

The binding of compounds or inhibition of binding of endothelin toET_(B) receptors can be assessed by measuring the inhibition ofendothelin-1-mediated release of prostacyclin, as measured by its majorstable metabolite, 6-keto PGF_(1α), from cultured bovine aorticendothelial cells (see, e.g., Filep et al. (1991) Biochem. and BiophysRes. Commun. 177: 171-176). Thus, the relative affinity of the compoundsfor different endothelin receptors may be evaluated by determining theinhibitory dose response curves using tissues that differ in receptorsubtype.

Using such assays, the relative affinities of the compounds for ET_(A)receptors and ET_(B) receptors have been and can be assessed. Those thatpossess the desired properties, such as specific inhibition of bindingof endothelin-1, are selected. The selected compounds that exhibitdesirable activities may be therapeutically useful and are tested forsuch uses using the above-described assays from which in vivoeffectiveness may be evaluated (see, e.g., U.S. Pat. No. 5,248,807; U.S.Pat. No. 5,240,910; U.S. Pat. No. 5,198,548; U.S. Pat. No. 5,187,195;U.S. Pat. No. 5,082,838; U.S. Pat. No. 5,230,999; published CanadianApplication Nos. 2,067,288 and 2071193; published Great BritainApplication No. 2,259,450; Published International PCT Application No.WO 93/08799; Benigi et al. (1993) Kidney International 44:440-444; andNirei et al. (1993) Life Sciences 52:1869-1874). Compounds that exhibitin vitro activities that correlate with in vivo effectiveness will thenbe formulated in suitable pharmaceutical compositions and used astherapeutics.

The compounds also may be used in methods for identifying and isolatingendothelin-specific receptors and aiding in the design of compounds thatare more potent endothelin antagonists or agonists or that are morespecific for a particular endothelin receptor.

2. Isolation of Endothelin Receptors

A method for identifying endothelin receptors is provided. In practicingthis method, one or more of the compounds is linked to a support andused in methods of affinity purification of receptors. By selectingcompounds with particular specificities, distinct subclasses of ETreceptors may be identified.

One or more of the compounds may be linked to an appropriate resin, suchas Affi-gel, covalently or by other linkage, by methods known to thoseof skill in the art for linking endothelin to such resins (see, Schvartzet al. (1990) Endocrinology 126: 3218-3222). The linked compounds can bethose that are specific for ET_(A) or ET_(B) receptors or other subclassof receptors.

The resin is pre-equilibrated with a suitable buffer generally at aphysiological pH (7 to 8). A composition containing solubilizedreceptors from a selected tissue are mixed with the resin to which thecompound is linked and the receptors are selectively eluted. Thereceptors can be identified by testing them for binding to an endothelinisopeptide or analog or by other methods by which proteins areidentified and characterized. Preparation of the receptors, the resinand the elution method may be performed by modification of standardprotocols known to those of skill in the art (see, e.g., Schvartz et al.(1990) Endocrinology 126: 3218-3222).

Other methods for distinguishing receptor type based on differentialaffinity to any of the compounds herein are provided. Any of the assaysdescribed herein for measuring the affinity of selected compounds forendothelin receptors may also be used to distinguish receptors subtypesbased on affinity for particular compounds provided herein. Inparticular, an unknown receptor may be identified as an ET_(A) or ET_(B)receptor by measuring the binding affinity of the unknown receptor for acompound provided herein that has a known affinity for one receptor overthe other. Such preferential interaction is useful for determining theparticular disease that may be treated with a compound prepared asdescribed herein. For example, compounds with high affinity for ET_(A)receptors and little or no affinity for ET_(B) receptors are candidatesfor use as hypertensive agents; whereas, compounds that preferentiallyinteract with ET_(B) receptors are candidates for use as anti-asthmaagents.

D. Formulation and Administration of the Compositions

Effective concentrations of one or more of the sulfonamide compounds offormula I or II or pharmaceutically acceptable salts, esters or otherderivatives thereof are mixed with a suitable pharmaceutical carrier orvehicle.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as tween, or dissolution in aqueous sodium bicarbonate. Derivativesof the compounds, such as salts of the compounds or prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

The concentrations or the compounds are effective for delivery of anamount, upon administration, that ameliorates the symptoms of theendothelin-mediated disease. Typically, the compositions are formulatedfor single dosage administration.

Upon mixing or addition of the sulfonamide compound(s), the resultingmixture may be a solution, suspension, emulsion or the like. The form ofthe resulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe selected carrier or vehicle. The effective concentration issufficient for ameliorating the symptoms of the disease, disorder orcondition treated and may be empirically determined.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients.

The active compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid, semi-liquid or solid form andare formulated in a manner suitable for each route of administration.Preferred modes of administration include oral and parenteral modes ofadministration.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in known in vitro and in vivo systems (see, e.g.,U.S. Pat. No. 5,114,918 to Ishikawa et al.; EP A1 0 436 189 to BANYUPHARMACEUTICAL CO., LTD (Oct. 7, 1991); Borges et al. (1989) Eur. J.Pharm. 165: 223-230;: Filep et al. (1991) Biochem. Biophys. Res. Commun.177: 171-176) and then extrapolated therefrom for dosages for humans.

The concentration of active compound in the drug composition will dependon absorption, inactivation and excretion rates of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to treat the symptoms of hypertension. Theeffective amounts for treating endothelin-mediated disorders areexpected to be higher than the amount of the sulfonamide compound thatwould be administered for treating bacterial infections.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 0.1 ng/ml to about50-100 μg/ml. The pharmaceutical compositions typically should provide adosage of from about 0.01 mg to about 2000 mg of compound per kilogramof body weight per day. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at intervals of time. It is understood that the precisedosage and duration of treatment is a function of the disease beingtreated and may be determined empirically using known testing protocolsor by extrapolation from in vivo or in vitro test data. It is to benoted that concentrations and dosage values may also vary with theseverity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions, and that the concentration rangesset forth herein are exemplary only and are not intended to limit thescope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a binder,such as microcrystalline cellulose, gum tragacanth and gelatin; anexcipient such as starch and lactose, a disintegrating agent such as,but not limited to, alginic acid and corn starch; a lubricant such as,but not limited to, magnesium stearate; a glidant, such as, but notlimited to, colloidal silicon dioxide; a sweetening agent such assucrose or saccharin; and a flavoring agent such as peppermint, methylsalicylate, and fruit flavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. Forexample, if the compound is used for treating asthma or hypertension, itmay be used with other bronchodilators and antihypertensive agents,respectively.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol or other syntheticsolvent; antimicrobial agents, such as benzyl alcohol and methylparabens; antioxidants, such as ascorbic acid and sodium bisulfite;chelating agents, such as ethylenediaminetetraacetic acid (EDTA);buffers, such as acetates, citrates and phosphates; and agents for theadjustment of tonicity such as sodium chloride or dextrose. Parentalpreparations can be enclosed in ampules, disposable syringes or multipledose vials made of glass, plastic or other suitable material.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof. Liposomalsuspensions, including tissue-targeted liposomes, may also be suitableas pharmaceutically acceptable carriers. These may be prepared accordingto methods known to those skilled in the art. For example, liposomeformulations may be prepared as described in U.S. Pat. No. 4,522,811.

The active compounds may be prepared with carriers that protect thecompound against rapid elimination from the body, such as time releaseformulations or coatings. Such carriers include controlled releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of such formulations are known to those skilled in theart.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Suchsolutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts. The compounds may be formulated as aerosols fortopical application, such as by inhalation (see, e.g., U.S. Pat. Nos.4,044,126, 4,414,209, and 4,364,923, which describe aerosols fordelivery of a steroid useful for treatment inflammatory diseases,particularly asthma).

Finally, the compounds may be packaged as articles of manufacturecontaining packaging material, a compound provided herein, which iseffective for antagonizing the effects of endothelin, ameliorating thesymptoms of an endothelin-mediated disorder, or inhibiting binding of anendothelin peptide to an ET receptor with an IC₅₀ of less than about 10μM, within the packaging material, and a label that indicates that thecompound or salt thereof is used for antagonizing the effects ofendothelin, treating endothelin-mediated disorders or inhibiting thebinding of an endothelin peptide to an ET receptor.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

EXAMPLE 1

N-(3,4-Dimethyl-5-isoxazolyl)-4-biphenylsulfonamide

(a) 4-Biphenylsulfonyl Chloride

4-Biphenylsulfonic acid (3.0 g, 12.8 mmol) was heated at 70° C. withphosphorus oxychloride (1.30 ml, 14.0 mol) for 2 h. Excess phosphorusoxychloride was removed under reduced pressure. The residue wasdecomposed with ice water and extracted with ethyl acetate. The extractwas washed with 5% sodium bicarbonate solution, dried over anhydrousmagnesium sulfate and concentrated to yield 2.9 g of crude4-biphenylsulfonyl chloride.

(b) N-(3,4-Dimethyl-5-isoxazolyl)-4-biphenylsulfonamide

The 4-biphenylsulfonyl chloride from step (a) was added to a solution of5-amino-3,4-dimethylisoxazole (250 mg, 2.2 mmol) and4-(dimethyl)aminopyridine (5 mg) in dry pyridine (2.0 ml). The reactionmixture was stirred at room temperature for 4 h. Pyridine was removedunder reduced pressure and the residue was partitioned between water andethyl acetate. The organic layer was washed with 1N HCl (2×25 ml), brine(25 ml) and dried over anhydrous magnesium sulfate. Evaporation of thesolvents left an oily residue that, after purification by columnchromatography over silica gel (1% methanol in chloroform as eluent),yielded 337 mg (45%) of a white solid. Recrystallization from ethylacetate/hexanes gave white crystals, m.p. 154-155° C.

EXAMPLE 2

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide

(a) 5-Amino-4-bromo-3-methylisoxazole

5-Amino-3-methylisoxazole (0.98 g, 10 mmol) was dissolved in chloroform(15 ml) and cooled to 0° C. N-Bromosuccinimide (1.78 g, 10 mmoles) wasadded in small portions over a period of 10 min. The stirring wascontinued for another 10 minutes at 0° C. The reaction mixture wasdiluted with chloroform (50 ml), washed with water (2×50 ml) and theorganic layer was dried over magnesium sulfate. Removal of the solventunder reduced pressure gave the crude product, which was purified bycolumn chromatography using 9:1, hexanes/ethyl acetate as the eluent, togive 5-amino-4-bromo-3-methylisoxazole (1.55 g, 87% yield).

(b)N-(4-Biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide

5-Amino-4-bromo-3-methylisoxazole (0.179 g, 1.0 mmol) was dissolved indry pyridine (2 ml). 4-Biphenylsulfonyl chloride (0.509 g, 2.2 mmol) wasadded with stirring at ambient temperature. N,N-dimethylaminopyridine (5mg) was added, and stirring was continued at 50° C. for 16 h. Thereaction mixture was diluted with dichloromethane (75 ml), washed with1N HCl (2×50 ml) and the organic phase was dried over magnesium sulfate.The solvent was removed under reduced pressure to yield a crude product,which was purified by column chromatography using 8:2, hexanes/ethylacetate, to give 0.390 g (60% yield) of N-(4-bphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide.

(c) N-(4-Bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide

N-(4-biphenylsulfonyl)-N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide(0.150 g, 0.233 mmol) was dissolved in tetrahydrofuran (THF). Sodiumhydroxide (0.120 g, 3.0 mmol) was added and the solution was warmed to45° C. to dissolve the sodium hydroxide. Stirring was continued for 20min. Tetrahydrofuran was removed under reduced pressure. The residue wasdissolved in water, cooled to 0° C. and acidified to pH 3-4 withconcentrated HCl. The solid precipitate was filtered off and dried invacuo to give N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide(94% yield), which was further purified by recrystallization fromchloroform/hexanes, m.p. 133-1350 C.

EXAMPLE 3

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide

N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide was prepared,using the method described in Example 1b, from5-amino-3,4-dimethylisoxazole and 2-benzofuransulfonyl chloride in 32%yield. Purification was achieved by recrystallization fromchloroform/hexanes to give a white “cotton-like” solid, m.p. 173-175° C.(dec.).

EXAMPLE 4

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide wasprepared in the same manner as described in Example 2b from5-amino-4-methyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonylchloride in 78% yield. Purification was achieved by recrystallizationfrom methanol/water to give a white solid, m.p. 139-140° C.

EXAMPLE 5

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide

N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide wasprepared, in the same manner as described in Example 2b, from5-amino-4-tridecyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonylchloride in 81% yield. Purification was achieved by recrystallizationfrom methanol/water to give an off white solid, m.p. 115-116° C.

EXAMPLE 6

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide

N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide wasprepared, as described in Example 2, from5-amino-4-methyl-3-trifluoromethylisoxazole and 4-biphenylsulfonylchloride in 78% yield. Purification was achieved by recrystallizationfrom ethyl acetate/hexanes to give a white solid, m.p. 139-140° C.

EXAMPLE 7

N-(4-Bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide

(a) 3-Amino-4-bromo-5-methylisoxazole

3-Amino-5-methylisoxazole (1.96 g, 20 mmol) was dissolved in chloroform(10 ml) and cooled to 0° C. N-Bromosuccinimide (3.56 g, 20 mmol) wasadded in small portions over a period of 10 min. The stirring wascontinued for another 15 minutes at 0° C. The reaction mixture wasdiluted with chloroform (100 ml), washed with water (2×50 ml) and theorganic layer was dried over magnesium sulfate. Removal of the solventunder reduced pressure gave the crude product, which was purified bycolumn chromatography, using 9:1 hexanes/ethyl acetate as the eluent, togive 3-amino-4-bromo-5-methylisoxazole (1.40 g, 40% yield).

(b) N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide

N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide was prepared,using the method in Example 1b, from 3-amino-4-bromo-5-methylisoxazoleand 4-biphenylsulfonyl chloride in 5% yield. The crude product waspurified by column chromatography. After recrystallization from ethylacetate/hexanes, N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfonamide(m.p. 154-156° C.) was obtained in 51% yield.

EXAMPLE 8

N-(4-Chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide

(a) 5-Amino-4-chloro-3-methylisoxazole

Using the method in Example 2a, 5-amino-4-chloro-3-methylisoxazole wasprepared from 5-amino-3-methylisoxazole and N-chlorosuccinimide in 90%yield.

(b) N-(4-Chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide

Sodium hydride (188 mg, 4.4 mmol) was suspended in dry THF (1 ml) andcooled to 0° C. A solution of 5-amino-4-chloro-3-methylisoxazole (mg,mmol) in dry THF (1 ml) was added with stirring. Once the addition wascomplete, the reaction mixture was warmed to room temperature for 10min. The solution was recooled to 0° C., and 4-biphenylsulfonyl chloride(0.283 ml, 2.2 mmol) was added. Stirring was continued at 25° C. for 2h. Excess sodium hydride was decomposed by the addition of methanol (0.4ml) followed by water (0.5 ml). The THF was removed under reducedpressure and the residue was dissolved in water (20 ml) and basified byaddition of sodium hydroxide (pH 9-10). Neutral impurities were removedby extraction with ethyl acetate (2×10 ml). The aqueous layer wasacidified to pH 2-3 using concentrated HCl and extracted with ethylacetate (3×10 ml). The combined organic layer was dried over magnesiumsulfate. Removal of the solvent gaveN-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide in 83% yield.This product was purified by recrystallization from ethylacetate/hexanes as a white solid, m.p. 129-132° C.

EXAMPLE 9

2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,5-dimethoxybenzenesulfonyl chloride according to the proceduresdescribed in Example 8 (see, also Example 30), below. The crude productwas purified by recrystallization from ethyl acetate/hexanes to give acrystalline solid, m.p. 118-120°, yield 58%.

EXAMPLE 10

N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide

A. 2-Biphenylsulfonyl Chloride

2-Bromobiphenyl (2.33 g, 10 mmol) was dissolved in ether (10 ml) andcooled to −78° C. n-Butyllithium (2.5 M solution in hexane, 4.8 ml, 12mmol) was added dropwise under constant stirring and an argonatmosphere. The resultant reaction mixture was stirred at −70° C. to−60° C. for 1 h. The reaction mixture was cooled to −78° C. and sulfurylchloride (0.88 ml, 11 mmol) was added dropwise. After addition, thereaction mixture was allowed to attain ambient temperature slowly andstirred for 1 h. The reaction mixture was diluted with ethyl acetate (50ml), washed with water and the organic layer dried over anhydrous MgSO₄.Removal of the solvent under reduced pressure gave a crude product,which was purified by column chromatography, using hexane followed by 5%ethyl acetate in hexane as eluent, to give 2-biphenylsulfonyl chlorideas a solid (1.3 g, 51% yield).

B. N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared inthe same manner as described in Example 8b from5-amino-4-bromo-3-methylisoxazole and 2-biphenylsulfonyl chloride in 71%yield. Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 145-147° C.

EXAMPLE 11

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared inthe same manner as described in Example 10 from5-amino-4-chloro-3-methylisoxazole and 2-biphenylsulfonyl chloride in74% yield. Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 132-134° C.

EXAMPLE 12

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide

A. 3-Biphenylsulfonyl Chloride

3-Bromobiphenyl (1.5 g, 6.4 mmol) was dissolved in ether (15 ml) andcooled to −78° C. t-Butyllithium (1.7 M solution in hexane, 3.8 ml, 6.4mmol) was added dropwise under constant stirring and an argonatmosphere. The resultant reaction mixture was stirred at −10° C. to −5°C. for 6 h. The reaction mixture was cooled to −78° C. and sulfurylchloride (0.64 ml, 6.4 mmol) was added dropwise. After completion of theaddition, the reaction mixture was allowed to attain ambient temperatureslowly and stirred for 1 h. The reaction mixture was diluted with ethylacetate (50 ml), washed with water and the organic layer dried overanhydrous MgSO₄. Removal of the solvent under reduced pressure gavecrude product, which was purified by column chromatography, using hexanefollowed by 5% ethyl acetate in hexane as eluent, to give3-biphenylsulfonyl chloride as an oil (0.8 g, 49% yield).

B. N-(4-bromo-3-methyl-5-isoxazolyi)-3-biphenysulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared inthe same manner as described in Example 8b from5-amino-4-bromo-3-methylisoxazole and 3-biphenylsulfonyl chloride in 22%yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CN over 30 min.)to give a solid., m.p. 78-82° C.

EXAMPLE 13

N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared inthe same manner as described in Example 12 from5-amino-4-chloro-3-methylisoxazole and 3-biphenylsulfonyl chloride in63% yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CN over 30min.) to give a solid, m.p. 84-86° C.

EXAMPLE 14

N-(3-methyl-5-isoxazolyi)-4-(4-methylphenyl)benzenesulfonamide

(a) N-(3-methyl-5-isoxazolyi)-4-bromobenzenesulfonamide

4-brombenzenesulfonyl chloride (solid) was added, in five portions, to asolution of 3-methyl-5-aminoisoxazole (3.82 g, 40 mmol) in dry pyridine(30 ml). This was stirred at room temperature for 3 h and the pyridinewas removed under reduced pressure. The residue was dissolved in THF(300 ml) and a 5% NaOH solution (100 ml) was added. Stirring continuedfor 1 h at room temperature. The THF was removed under reduced pressureand the resultant residue was neutralized to pH 2 using concentratedhydrochloric acid. This was extracted with ethyl acetate (3×200 ml) andthe combined organic layer was dried over MgSO₄ and concentrated. Thecrude product was recrystallized using hexane/ethyl acetate givingN-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (9.2 g, 72% yield).

(b) N-(3-methyl-5-isoxazolyi)-4-(4-methylphenyl)benzenesulfonamide

Nitrogen was bubbled through a biphasic mixture of ethanol (15 ml),toluene (15 ml) and 2M sodium carbonate solution (15 ml).N-(3-methyl-5-isoxazolyl)-4-bromobenzene sulfonamide (0.951 g, 3 mmol),4-methylbenzeneboronic acid (0.56 g, 4 mmol) andtetrakistriphenylphosphine palladium (O) (300 mg) were added. Thereaction mixture was kept at 80° C., under a N₂ atmosphere for 24 h,with stirring, and was then diluted with water (50 ml) and extractedwith ether (50 ml) to remove neutral impurities and excess4-methylbenzeneboronic acid. The aqueous phase was neutralized to pH 2using concentrated hydrochloric acid and the resultant solid wasfiltered. This was dried under vacuum and recrystallized usinghexanelethyl acetate givingN-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (1.0 g,100% yield, 30 m.p. 194-198° C.).

EXAMPLE 15

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide

N-bromosuccinimide (NBS) (0.178 g, 1 mmol), in one lot, was added to astirred suspension ofN-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327g,1 mmol, Example 14b) in chloroform (12 ml). The reaction mixture wasstirred for 10 min then diluted with dichloromethane (50 ml). This waswashed with water (2×50 ml). The organic layer was dried over MgSO₄ andconcentrated. The crude product was recrystallized using hexane/ethylacetate givingN-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide(350 mg, 86% yield, m.p. 153-156° C.).

EXAMPLE 16

N-(4-chloro-3-methyl-5-isoxazolyi)-4-(4-methylphenyl)benzenesulfonamide

N-chlorosuccinimide (0.266 g, 2 mmol) was added, in one lot, to astirred suspension ofN-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327g,1 mmol, Example 14b) in chloroform (10 ml) and stirred at roomtemperature for 2 h The reaction mixture was diluted withdichloromethane (50 ml) and washed with water (2×50 ml). The organiclayer was dried over MgSO₄ and concentrated. The crude product waspurified by column chromatography using ethyl acetate as eluent to giveN-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide[210 mg, 58% yield, m.p. 260° C. (de coup)].

EXAMPLE 17

N-(3-methyl-5-isoxazolyi)-4-[(4-trifluoromethyl)phenyl]benzenesulfonamide

N-(3-methyl-5-isoxazolyl)-4-(4-trifluoromethylphenyl)benzenesulfonamidewas prepared in the same manner as described in Example 14b, usingN-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and4-trifluoromethylbenzeneboronic acid resulting in the final product in a78% yield, m.p. 150-153° C. The product was recrystallized using anacetonirile and water mixture.

EXAMPLE 18

N-(4-bromo-3-methyl-5-isoxazolyl)-4-[(4-trifluoromethyl)phenyl]benzenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-[(4-trifluoromethyl)phenyl]benzenesulfonamidewas prepared in the same manner as described in Example 15, usingN-(3-methyl-5-isoxazolyl)-4-(4-trifluoromethylphenyl)benzenesulfonamide(Example 17) and NBS (reaction time 30 min at room temperature). Thecrude product was purified by column chromatography on silica gel usingethyl acetate as eluent resulting in the final product in 56% yield,m.p. 113-117° C.

EXAMPLE 19

N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide

N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide wasprepared in the same manner as described in Example 14b, usingN-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 14a) and4-methoxybenzeneboronic acid resulting in an 82% yield of the finalproduct, m.p. 194-196° C. The product was recrystallized usinghexane/ethyl acetate.

EXAMPLE 20

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl) benzenesulfonamidewas prepared in the same manner as described in Example 15 usingN-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide (Example19) and NBS (reaction time 30 min at room temperature). The crudeproduct was purified by column chromatography on silica gel using ethylacetate as eluent giving the final product in 78% yield, m.p. 208° C.(dec). The product was recrystallized using hexane/ethyl acetate.

EXAMPLE 21

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide

(a) N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide

N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl) benzenesulfonamide wasprepared in the same manner as described in Example 14b, usingN-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 14a) and3-methoxybenzeneboronic acid resulting in a 77% yield.

(b)N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamidewas prepared in the same manner as described in Example 15 usingN-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide and NBS(reaction time 30 min at room temperature). The crude product waspurified by column chromatography on silica gel using ethyl acetate aseluent giving the final product, after recrystallization usinghexane/ethyl acetate, in 75% yield, m.p. 140-144° C.

EXAMPLE 22

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide

(a) N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide

N-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide wasprepared in the same manner as described in Example 14 usingN-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and2-methoxybenzeneboronic acid resulting in an 81% yield of the finalproduct.

(b)N-(4-bromo-3-methyl-5-isoxozolyl)-4-(2-methoxyphenyl)benzenesulfonamide

N-(4-bromo-3-methyl-5-isoxozolyl)-4-(2-methoxyphenyl) benzenesulfonamidewas prepared in the same manner as described in Example 15, usingN-(3-methyl-5-isoxazolyl)-4-(2-methoxyphenyl)benzenesulfonamide and NBS(reaction time 30 min at room temp.) The crude product was purified bycolumn chromatography on silica gel using ethyl acetate as eluent togive the final product in 68% yield, m.p. 205-209° C.

EXAMPLE 23

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesulfonamide

(a)N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesulfonamide

N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesulfonamidewas prepared in the same manner as described in Example 14b, usingN-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and3,4-methylenedioxyphenylboronic acid resulting in a 67% yield of finalproduct.

(b)N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesulfonamidewas prepared in the same manner as described in Example 15, usingN-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesulfonamideand NBS in THF as solvent resulting in a 35% yield. The crude productwas purified by HPLC, m.p. 172-174° C.

EXAMPLE 24

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide

(a) N-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide

N-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide wasprepared in the same manner as described in Example 14b, usingN-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 14a) and3-methylbenzeneboronic acid resulting in an 82% yield.

(b)N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methylphenyl) benzenesulfonamidewas prepared in the same manner as described in Example 15, usingN-(3-methyl-5-isoxazolyl)-4-(3-methylphenyl)benzenesulfonamide and NBSin THF as solvent (reaction time 30 min at room temperature). The crudeproduct was purified by HPLC resulting in a 31% yield of the finalproduct, m.p. 186-189° C.

EXAMPLE 25

N-(4-Bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

(a) 5-Amino-4-bromo-3-methylisoxazole

5-Amino-3-methylisoxazole (0.98 g, 10 mmol) was dissolved in chloroform(15 ml) and cooled to 0° C. N-Bromosuccinimide (1.78 g, 10 mmoles) wasadded in small portions over a period of 10 min. The stirring wascontinued for another 10 minutes at 0° C. The reaction mixture wasdiluted with chloroform (50 ml), washed with water (2×50 ml) and theorganic layer was dried over magnesium sulfate. Removal of the solventunder reduced pressure gave the crude product which was purified bycolumn chromatography using a 9:1 mixture of hexanes/ethyl acetate aseluent to give 5-amino-4-bromo-3-methylisoxazole (1.55 g, 87 % yield).

(b) N-(4-Bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) indry THF (1 ml) was added to a suspension of sodium hydride (60%dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0° C.After stirring at 0-5° C. for 10 min., the reaction was warmed to roomtemperature for 10 min. to complete the reaction. The reaction mixturewas re-cooled to 0° C. and benzenesulfonyl chloride (0.283 ml, 2.2 mmol)was added slowly. Stirring was continued for 20 min. at 0-5° C. Excesssodium hydride was decomposed by the addition of methanol (0.4 ml)followed by water (0.5 ml). The solvent was removed under reducedpressure. The residue was dissolved in water (20 ml), basified to pH 8-9by the addition of sodium hydroxide and extracted with ethyl acetate(2×10 ml) to remove the neutral impurities. The aqueous layer wasacidified with concentrate HCI (pH 2-3) and extracted with ethyl acetate(3×10 ml) The combined organic layer was dried over magnesium sulfateand concentrated under reduced pressure to giveN-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide. The pure materialwas obtained by recrystallization using hexanes/ethyl acetate (0.59 g,93% yield), m.p. 142-144° C.

EXAMPLE 26

N-(4-Bromo-5-tert-butyl-3-isoxazolyl)benzenesulfonamide

(a) 3-Amino-4-bromo-5-tert-butylisoxazole

This compound was prepared from 3-amino-5-tert-butylisoxazole andN-bromosuccinimide as described in Example 25a in 91% yield, R_(f) 0.27(3:1 hexanes/ethyl acetate).

(b) N-(4-Bromo-5-tert-butyl-3-isoxazolyl)benzenesulfonamide

3-Amino-4-bromo-5-tert-butylisoxazole (219 mg, 1.0 mmol) was dissolvedin dry pyridine (1 ml). Benzenesulfonyl chloride (0.14 ml, 1.1 mmol) and4-dimethylamino-pyridine (5 mg) were added and the solution was stirredat 50° C. for 6 h. The reaction mixture was diluted with dichloromethane(75 ml), washed with 1N HCl (50 ml) and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography (9:1 hexanes/ethylacetate). A crystalline solid was obtained after recrystallization fromethyl acetate/hexanes, m.p. 139-141° C.

EXAMPLE 27

N-(3-Methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide

(a)N-(Benzenesulfonyl)-N-(3-methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide

5-Amino-3-methyl-4-phenylisoxazole (0.174 g, 1.0 mmol) was dissolved indry pyridine (2 ml). Benzenesulfonyl chloride (0.389 g, 2.2 mmol) wasadded with stirring at ambient temperature. N,N-Dimethylaminopyridine (5mg) was added and stirring was continued at 50° C. for 4 h. The reactionmixture was diluted with dichloromethane (75 ml), washed with 1N HCl(2×50 ml) and the organic phase was dried over magnesium sulfate. Thesolvent was removed under reduced pressure to yield a crude product thatwas purified by column chromatography using 5:1, hexanes/ethyl acetateto give 0.390 g (85% yield) ofN-benzenesulfonyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide.

(b) N-(3-Methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide

N-Benzenesulfonyl-N-(3-methyl-4-phenyl-5-isoxazolyl) benzenesulfonamide(300 mg, 0.66 mmol) was dissolved in methanol. Potassium hydroxide (300mg, 5.5 mmol) was added and the solution was warmed to 45° C. todissolve the sodium hydroxide. Stirring was continued for 20 min.Methanol was removed under reduced pressure. The residue was dissolvedin water, cooled to 0° C. and acidified to pH 3-4 with concentrated HCl.The solid precipitate was extracted with ethyl acetate, dried andevaporated in vacuo to give 210 mg (100% yield) ofN-(3-methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide, which was furtherpurified by recrystallization from ethyl acetate/hexanes, m.p. 124-126°C.

EXAMPLE 28

N-(4-Bromo-3-phenyl—5-isoxazolyl)benzenesulfonamide

This compound was prepared from benzenesulfonyl chloride and5-amino-4-bromo-3-phenylisoxazole according to the method in Example 25bin 36% yield. Recrystallization from methanol gave a yellow solid, m.p.113-115° C.

EXAMPLE 29

N-(4-Bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide

(a) 5-Amino-4-bromo-3-tert-butylisoxazole

5-Amino-4-bromo-3-tert-butylisoxazole was prepared from5-amino-3-tert-butylisoxazole and N-bromosuccinimide in 64% yield asdescribed in Example 25a.

(b)N-Benzenesulfonyl-N-(4-Bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide

5-Amino-4-bromo-3-tert-butylisoxazole (440 mg, 2.0 mmol) was dissolvedin dry pyridine (2 ml). Benzenesulfonyl chloride (344 mg, 2.0 mmol) and4-dimethylamino-pyridine (5 mg) was added and the reaction was stirredat 50° C. for 16 h. The reaction mixture was diluted with ethyl acetate(20 ml), washed with 1N HCl (2×10 ml) and the organic phase was driedover magnesium sulfate. The solvent was removed under reduced pressureto yield a crude product, which was recrystallized from ethylacetate/hexanes to give 300 mg (60% yield) ofN-benzenesulfonyl-N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide.

(c) N-(4-Bromo-3-tert-butyl-5-isoxazolyl)benzenelsulfonamide

N-Benzenesulfonyl-N-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide (80 mg, 0.16 mmol) was dissolved in methanol (2 ml).Sodium hydroxide (0.120 g, 3.0 mmol) in methanol was added and thesolution was stirred at 45° C. for 20 min. Methanol was removed underreduced pressure. The residue was dissolved in water, cooled to 0° C.and acidified to pH 3-4 with concentrated hydrochloric acid andextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and concentrated in vacuo to giveN-(4-bromo-3-tert-butyl-5-isoxazolyl)benzenesulfonamide in 94% yield.Further purification was achieved by recrystallization frommethanol/water, giving an off white solid, m.p. 108-109° C.

EXAMPLE 30

4-tert-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) indry THF (1 ml) was added to a suspension of sodium hydride (60%dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5°C. After stirring at 0-5° C. for 10 min, the reaction was warmed to roomtemperature for 10 min. to complete the reaction. The reaction mixturewas re-cooled to 0° C. and 4-tert-butylbenzenesulfonyl chloride (512 mg,2.2 mmol) was added slowly. Stirring was continued for 20 min at 0-5° C.Excess sodium hydride was decomposed by the addition of methanol (0.4ml) followed by water (0.5 ml). The mixture was acidified withhydrochloric acid and extracted with dichloromethane. Theextract wasdried over anhydrous magnesium sulfate and the solvent was removed underreduced pressure to give a crude product, which was purified byrecrystallization from ethyl acetate/hexanes to give a white solid in21% yield, m.p. 170° C. (dec.).

EXAMPLE 31

4-iso-Propyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-iso-Pro pyl-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide wasprepared in the same manner as described in Example 30 from5-amino-4-bromo-3-methylisoxazole and 4-iso-propylbenzenesulfonylchloride in 77% yield. Purification was achieved by recrystallizationfrom ethyl acetate/hexanes to give a crystalline solid, m.p. 130-133° C.

EXAMPLE 32

4-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-Bromo-N-(4-bromo-3-methy l-5-isoxazolyl)benzenesulfonamide wasprepared in the same manner as described in Example 30 from5-amino-4-bromo-3-methylisoxazole and 4-bromobenzenesulfonyl chloride in74% yield. Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 146-149° C.

EXAMPLE 33

4-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared in the same manner as described in Example 30 from5-amino-4-bromo-3-methylisoxazole and 4-fluorobenzenesulfonyl chloridein 71% yield. Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 142-144° C.

EXAMPLE 34

3-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

3-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was preparedin the same manner as described in Example 30 from5-amino-4-bromo-3-methylisoxazole and 3-nitrobenzenesulfonyl chloride in55% yield. Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 151-153° C.

EXAMPLE 35

N-(4-Bromo-5-methyl-3-isoxazolyl)benzenesulfonamide

(a) 3-Amino-4-bromo-5-methylisoxazole

3-Amino-5-methylisoxazole (1.96 g, 20 mmol) was dissolved in chloroform(10 ml) and cooled to 0° C. N-Bromosuccinimide (3.56 g, 20 mmol) wasadded in small portions over a period of 10 min. The stirring wascontinued for another 15 minutes at 0° C. The reaction mixture wasdiluted with chloroform (100 ml), washed with water (2×50 ml) and theorganic layer was dried over magnesium sulfate. Removal of the solventunder reduced pressure gave the crude product, which was purified bycolumn chromatography using 9:1, hexanes/ethyl acetate as eluent, togive 3-amino-4-bromo-5-methylisoxazole (1.40 g, 40% yield).

(b) N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide andN-(benzenesulfonyl)N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide

3-Amino-4-bromo-5-methylisoxazole (5.31 g, 30 mmol) was dissolved in drypyridine (30 ml). Benzenesulfonyl chloride (5.24 ml, 42 mmol) was addeddropwise with stirring at ambient temperature.N,N-(Dimethyl)aminopyridine (100 mg) was added and stirring wascontinued at 50° C. for 25 h. The reaction mixture was diluted withdichloromethane (200 ml), washed with 1N HCl (6×100 ml) and the organicphase was dried over magnesium sulfate. The solvent was removed underreduced pressure to yield a crude product which was purified by columnchromatography using 9:1, hexanes/ethyl acetate as eluent to giveN-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide(7 g, 51% yield, R_(f)=0.27 using 3:1, hexanes/ethyl acetate as eluent)as a solid.

Further elution with ethyl acetate gaveN-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide (2 g, 21% yield,R_(f)=0.08 with 3:1 hexanes/ethyl acetate as eluent), m.p. 128-130° C.

(c) N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide

Sodium hydroxide (1.3 g, 30.6 mmol) was added to a solution ofN-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzene-sulfonamide(7 g, 15.3 mmol, prepared as described in (a)) in methanol (100 ml). Theresulting solution was stirred at 25° C. for 30 h. Excess methanol wasremoved under reduced pressure. The residue was dissolved in water (50ml) and acidified (pH 3-4) by the addition of concentrated HCl withcooling. The mixture was extracted with dichloromethane (2×100 ml) andthe combined organic layer was dried over anhydrous magnesium sulfate.Removal of the solvent gaveN-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide which was purifiedby crystallization from ethyl acetate/hexanes (4.5 g, 92% yield). Thecompound is identical to the one isolated in step (b).

EXAMPLE 36

N-(4-Bromo-5-methyl-3-isoxazolyl)-1-naphthalenesulfonamide

N-(4-Bromo-5-methyl-3-isoxazolyl)-1-naphthalenesulfonamide was preparedfrom 3-amino-4-bromo-5-methylisoxazole and 1-naphthalenesulfonylchloride as described in Example 26 in 51% yield. Recrystallization fromethyl acetate/hexanes gave a crystalline solid, m.p. 167-170° C.

EXAMPLE 37

N-(4-Chloro-3-methyl-5-isoxazolyl)benzenesuolfonamide

(a) 5-Amino-4-chloro-3-methylisoxazole

Using the method in Example 25a, 5-amino-4-chloro-3-methylisoxazole wasprepared in 90% yield from 5-amino-3-methylisoxazole andN-chlorosuccinimide.

(b) N-(4-Chloro-3-methyl-5-isoxazolyl)benzenesuolfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)benzenesuolfonamide was preparedaccording to the method in Example 25b from5-amino-4-chloro-3-methylisoxazole and benzenesulfonyl chloride in 84%yield. The crude product was purified by recrystallization usinghexanes/ethyl acetate, m.p. 140-143° C.

EXAMPLE 38

N-(4-Chloro-5-methyl-3-isoxazolyl)benzenesulfonamide

(a) 3-Amino-4-chloro-5-methylisoxazole

This compound was prepared from 3-amino-5-methylisoxazole andN-chlorosuccinimide as described in Example 25a except the reaction waschanged to 35° C and the reaction time was extended to 12 h. The yieldwas 62%, R_(f) 0.17 (3:1 hexanes/ethyl acetate).

(b) N-(4-Chloro-5-methyl-3-isoxazolyl)benzenesulfonamide

N-(4-chloro-5-methyl-3-isoxazolyl)benzenesulfonamide was prepared from3-amino-4-chloro-5-methylisoxazole and benzenesulfonyl chloride asdescribed in Example 26b in 40% yield. The crude product was purified bycolumn chromatography with 10-100% ethyl acetate/hexanes as eluent. Acrystalline solid was obtained after recrystallization from ethylacetate/hexanes, m.p. 139-141° C. 3-Amino-4-chloro-5-methylisoxazole(25% recovery) andN-(benzenesulfonyl)-N-(4-chloro-5-methyl-3-isoxazolyl)benzenesulfonamide(7% yield) were also obtained as less polar products.

EXAMPLE 39

4-lodo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-lodo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was preparedfrom 5-amino-4-bromo-3-methylisoxazole and 4-iodobenzenesulfonylchloride according to the procedures described in Example 25b. The crudeproduct was purified by recrystallization from ethyl acetate/hexanes togive a yellow powder, m.p. 166-173° C., yield 65%.

EXAMPLE 40

4-Chloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-Chloro-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and4-chlorobenzenesulfonyl chloride according to the procedures describedin Example 25b. The crude product was purified by recrystallization fromethyl acetate/hexanes to give a yellow powder, m.p. 145-150° C., yield93%.

EXAMPLE 41

N-(4-Bromo-3-ethyl-5-isoxazolyl)benzenesulfonamide

(a) 5-Amino-4-bromo-3-ethylisoxazole

5-Amino-4-bromo-3-ethylisoxazole was prepared from5-amino-3-ethylisoxazole and N-bromosuccinimide as described in Example25a.

(b) N-(4-Bromo-3-ethyl-5-isoxazolyl)benzenesulfonamide

N-(4-Bromo-3-ethyl-5-isoxazolyl) benzenesulfonamide was prepared from5-amino-4-bromo-3-ethylisoxazole and benzenesulfonyl chloride accordingto the procedures described in Example 25b. The crude product waspurified by recrystallization from ethyl acetate/hexanes to giveoff-white crystals, m.p. 90-93° C., yield 70%.

EXAMPLE 42

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-toluenesulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-toluenesulfonamide was prepared from5-amino-4-bromo-3-methylisoxazole and 4-toluenesulfonyl chlorideaccording to the procedures described in Example 25b. The crude productwas purified by recrystallization from ethyl acetate/hexanes to giveoff-white crystals, m.p. 169-172° C., yield 69%.

EXAMPLE 43

2,5-Dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2,5-Dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,5-di-methylbenzenesulfonyl chloride according to the proceduresdescribed in Example 25b. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give off-white crystals,m.p. 102-104° C., yield 81%.

EXAMPLE 44

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-toluenesulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-toluenesulfonamide was prepared from5-amino-4-bromo-3-methylisoxazole and 2-toluenesulfonyl chlorideaccording to the procedures described in Example 25b. The crude productwas purified by recrystallization from ethyl acetate/hexanes to givewhite crystalline solid, m.p. 93-96° C., yield 88%.

EXAMPLE 45

2-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2-fluorobenzenesulfonyl chloride according to the procedures describedin Example 25b. The crude product was purified by recrystallization fromethyl acetate/hexanes to give a white solid, m.p. 87-89° C., yield 44%.

EXAMPLE 46

3-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

3-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and3-fluorobenzenesulfonyl chloride according to the procedures describedin Example 25b. The crude product was purified by recrystallization fromethyl acetate/hexanes to give a light yellow solid, m.p. 125-128° C.,yield 88%.

EXAMPLE 47

2,5-Dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzenesulfonamide

2,5-Dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-chloro-3-methylisoxazole and2,5-dimethylbenzenesulfonyl chloride according to the proceduresdescribed in Example 25b. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a light yellowsolid, m.p. 92-93° C., yield 82%.

EXAMPLE 48

4-Acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-Acetamido-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and 4-acetylsulfinilylchloride according to the procedures described in Example 30. The crudeproduct was purified by recrystallization from ethyl acetate/hexanes togive a crystalline solid, m.p. 208-210° C., yield 56%.

EXAMPLE 49

4-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was preparedfrom 5-amino-4-bromo-3-methylisoxazole and 4-nitrobenzenesulfonylchloride according to the procedures described in Example 30. The crudeproduct was purified by recrystallization from ethyl acetate/hexanes togive a crystalline solid, m.p. 146-149° C., yield 34%.

EXAMPLE 50

4-Butoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-Butoxy-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and4-butoxybenzenesulfonyl chloride according to the procedures describedin Example 30. The crude product was purified by recrystallization fromethyl acetate/hexanes to give a crystalline solid, m.p. 98-100° C.,yield 33%.

EXAMPLE 51

3-Chloro-2-methyl-N-(4-Bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

3-Chloro-2-methyl-N-(4-Bromo-3-methyl-5-isoxazolyl)benzenesulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and3-chloro-2-methylbenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 185-187° C., yield 34%.

EXAMPLE 52

2,4,6-Trimeth.l-N-(4-bromo-3-methyl-5-isoxazolyi)benzenesulfonamide

2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,4,6-trimethylbenzenesulfonyl chloride according to the proceduresdescribed in Example 25b. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a pink solid, m.p.92-95° C., yield 64%

EXAMPLE 53

N-(4-bromo-3-methyl-5-isoxazolyl)-3-toluenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-toluenesulfonamide was prepared from5-amino-4-bromo-3-methylisoxazole and 3-toluenesulfonyl chlorideaccording to the procedures described in Example 30. The crude productwas purified by recrystallization from ethyl acetate/hexanes to give acrystalline solid, m.p. 138-140° C., yield 63%.

EXAMPLE 54

3-Chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

3-Chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and3-chloro-2,5-dimethylbenzenesulfonyl chloride according to theprocedures described in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 148-150° C., yield 71%.

EXAMPLE 55

2,5-Difluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2,5-Difluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and4-chlorobenzenesulfonyl chloride according to the procedures describedin Example 30. The crude product was purified by recrystallization fromethyl acetate/hexanes to give a crystalline solid, m.p. 123-125° C.,yield 62%.

EXAMPLE 56

2,3,4-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2,3,4-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,3,4-trichlorobenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p.110-113° C., yield 66%.

EXAMPLE 57

2,3-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2,3-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,3-dichlorobenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 166-169° C., yield 75%.

EXAMPLE 58

2,5-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide2,5-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,5-dichlorobenzenesulfonyl chloride according to the proceduresdescribed in Example 25b. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a yellow powder,m.p. 148-150° C., yield 53%.

EXAMPLE 59

5-Bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

5-Bromo-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and5-bromo-2-methoxybenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 192-195° C., yield 61%.

EXAMPLE 60

2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was preparedfrom 5-amino-4-bromo-3-methylisoxazole and 2-bromobenzenesulfonylchloride according to the procedures described in Example 30. The crudeproduct was purified by recrystallization from ethyl acetate/hexanes togive a crystalline solid, m.p. 84-86° C., yield 31%.

EXAMPLE 61

2-Cyano-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2-Cyano-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and4-chlorobenzenesulfonyl chloride according to the procedures describedin Example 30. The crude product was purified by recrystallization fromethyl acetate/hexanes to give a crystalline solid, m.p. 152-155° C.,yield 70%.

EXAMPLE 62

2,4,5-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2,4,5-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,4,5-trichlorobenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 179-182° C., yield 67%.

EXAMPLE 63

3,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

3,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and3,4-dichlorobenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 144-146° C., yield 60%.

EXAMPLE 64

3,4-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

3,4-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and3,4-dimethoxybenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 136-138° C., yield 64%.

EXAMPLE 65

2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide wasprepared from 5-amino-4-bromo-3-methylisoxazole and2,4-dichlorobenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 138-141° C., yield 46%.

EXAMPLE 66

N-(4-lodo-5-methyl-3-isoxazolyl)benzenesulfonamide

(a) 3-amino-4-lodo-5-methylisoxazole

3-Amino-4-iodo-5-methylisoxazole was prepared from3-amino-5-methylisoxazole and N-iodosuccinimide as described in Example50a in 46% yield, m.p. 115-117° C.

(b) N-(4-lodo-5-methyl-3-isoxazolyl)benzenesulfonamide

N-(4-lodo-5-methyl-3-isoxazolyl) benzenesulfonamide was prepared from3-amino-4-iodo-5-methylisoxazole and benzenesulfonyl chloride accordingto the procedures described in Example 25b. The crude product waspurified by recrystallization from ethyl acetate/hexanes to give a brownpowder m.p. 138-141° C., yield 46%.

EXAMPLE 67

4-Nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide4-Nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide was preparedfrom 5-amino-4-bromo-3-methylisoxazole and 4-nitrobenzenesulfonylchloride according to the procedures described in Example 25b. The crudeproduct was purified by recrystallization from ethyl acetate/hexanes togive a light tan solid, m.p. 161-163° C., yield 55%.

EXAMPLE 68

3-Nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide

3-Nitro-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide was preparedfrom 5-amino-4-bromo-3-methylisoxazole and 3-nitrobenzenesulfonylchloride according to the procedures described in Example 25b. The crudeproduct was purified by recrystallization from ethyl acetate/hexanes,resulting in an off white powder, m.p. 137-139° C., yield 72%.

EXAMPLE 69

4-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

4-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and4-trifluoromethylbenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 155-158° C., yield 72%.

EXAMPLE 70

3-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

3-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and3-trifluoromethylbenzenesulfonyl chloride according to the proceduresdescribed in Example 30. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 113-115° C., yield 83%.

EXAMPLE 71

Assays for Identifying Compounds that Exhibit Endothelin Antagonisticand/or Agonist Activity

Compounds that are potential endothelin antagonists are identified bytesting their ability to compete with ¹²⁵I-labeled ET-1 for binding tohuman ET_(A) receptors or ET_(B) receptors present on isolated cellmembranes. The effectiveness of the test compound as an antagonist oragonist of the biological tissue response of endothelin can also beassessed by measuring the effect on endothelin induced contraction ofisolated rat thoracic aortic rings. The ability of the compounds to actas antagonists or agonists for ET_(B) receptors can be assess by testingthe ability of the compounds are to inhibit endothelin-1 inducedprostacyclin release from cultured bovine aortic endothelial cells.

A. Endothelin Binding Inhibition—Binding Test #1: Inhibition of Bindingto ET_(A) Receptors

TE 671 cells (ATCC Accession No. HTB 139) express ET_(A) receptors.These cells were grown to confluence in T-175 flasks. Cells frommultiple flasks were collected by scraping, pooled and centrifuged for10 min at 190×g. The cells were resuspended in phosphate buffered saline(PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. Thesuspension was centrifuged at 4° C. at 57,800×g for 15 min, the pelletwas resuspended in 5 ml of buffer A (5 mM HEPES buffer, pH 7.4containing aprotinin (100 KIU/ml)) and then frozen and thawed once. 5 mlof Buffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCl₂ and 0.001%deoxyribonuclease Type 1) was added, the suspension mixed by inversionand then incubated at 37° C. for 30 minutes. The mixture was centrifugedat 57,800×g as described above, the pellet washed twice with buffer Aand then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/mI) to give a final protein concentration of 2 mg/mland stored at −70° C. until use.

The membrane suspension was diluted with binding buffer (30 mM HEPESbuffer, pH 7.4 containing 150 mM NaCl, 5mM MgCl₂, 0.5% Bacitracin) to aconcentration of 8 μg/50 μl. ¹²⁵I-endothelin-1 (3,000 cpm, 50 mL) wasadded to 50 μL of either: (A) endothelin-1 (for non specific binding) togive a final concentration 80 nM); (B) binding buffer (for totalbinding); or (C) a test compound (final concentration 1 nM to 100 μM).The membrane suspension (50 μL), containing up to 8 μg of membraneprotein, was added to each of (A), (B), or (C). Mixtures were shaken,and incubated at 4° C. for 16-18 hours, and then centrifuged at 4° C.for 25 min at 2,500×g. Alternatively, the incubation was conducted at24° C. When incubated at 24° C., the IC₅₀ concentrations are 2- to10-fold higher than when the incubation is conducted at 4° C. This, mustbe kept in mind when comparing IC₅₀ concentrations among compoundsprovided herein.

The supernatant, containing unbound radioactivity, was decanted and thepellet counted on a Genesys multiwell gamma counter. The degree ofinhibition of binding (D) was calculated according to the followingequation:${\% \quad D} = {100 - {\frac{(C) - (A)}{(B) - (A)} \times 100}}$

Each test was generally performed in triplicate.

B. Endothelin Binding Inhibition—Binding Test #2: Inhibition of Bindingto ET_(B) Receptors

COS7 cells were transfected with DNA encoding the ET_(B) receptor, Theresulting cells, which express the human ET_(B) receptor, were grown toconfluence in T-150 flasks. Membrane was prepared as described above.The binding assay was performed as described above using the membranepreparation diluted with binding buffer to a concentration of 1 μg/50μl.

Briefly, the COS7 cells, described above, that had been transfected withDNA encoding the ET_(B) receptor and express the human ET_(B) receptoron their surfaces were grown to confluence in T-175 flasks. Cells frommultiple flasks were collected by scraping, pooled and centrifuged for10 min at 190×g. The cells were resuspended in phosphate buffered saline(PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. Thesuspension was centrifuged at 4° C57,800×g for 15 min, the pellet wasresuspended in 5 ml of buffer A (5mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml)) and then frozen and thawed once. Five ml ofBuffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCl₂ and 0.001%deoxyribonuclease Type 1) was added, the suspension mixed by inversionand then incubated at 37° C. for 30 minutes. The mixture was centrifugedat 57,800×g as described above, the pellet washed twice with buffer Aand then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml) to give a final protein concentration of 2 mg/ml.

The binding assay was performed as described above using the membranepreparation diluted to give 1 μg/50 μl of binding buffer.

C. Test for Activity Against Endothelin-Induced Contraction of IsolatedRat Thoracic Aortic Rings

The effectiveness of the test compound as an antagonist or agonist ofthe biological tissue response of endothelin also is assessed bymeasuring the effect on endothelin induced contraction of isolated ratthoracic aortic rings (see, em, Borges et al. (1989) Eur. J. Pharmacol.165:223-230) or by measuring the ability to contract the tissue whenadded alone.

Compounds to be tested are prepared as 100 μM stocks. If necessary toeffect dissolution, the compounds are first dissolved in a minimumamount of DMSO and diluted with 150 mM NaCl. Because DMSC can causerelaxation of the aortic ring, control solutions containing varyingconcentrations of DMSO were tested.

The thoracic portion of the adult rat aorta is excised, the endotheliumabraded by gentle rubbing and then cut into 3 mm ring segments. Segmentsare suspended under a 2 g preload in a 10 ml organ bath filled withKrebs'—Henseleit solution saturated with a gas mixture of 95% O₂ and 5%CO₂ (118 mM NaCl, 4,7 mM KCl, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄, 25 mM NaHCO₃,2.5 mM CaCl₂, 10 mM D-glucose).

There is a correlation between activity as an antagonist ofendothelin-induced thoracic aortic ring contraction and activity as aninhibitor of binding of endothelin to endothelin receptors. The pA₂ is alinear function of the log of the IC₅₀.

D. Assay for Identifying Compounds That Have Agonist and/or AntagonisticActivity Against ET_(B) Receptors

1. Stimulation of Prostacyclin Release

Since endothelin-1 stimulates the release of prostacyclin from culturedbovine aortic endothelial cells, the compounds that have agonist orantagonist activity are identified by their ability to inhibitendothelin-1 induced prostacyclin release from such endothelial cells bymeasuring 6-keto PGF_(1α) substantially as described by (Filep et al.(1991) Biochem. Biophys. Res. Commun. 177 171-176. Bovine aortic cellsare obtained from collagenase-treated bovine aorta, seeded into cultureplates, grown in Medium 199 supplemented with heat inactivated 15% fetalcalf serum, and L-glutamine (2 mM), penicillin, streptomycin andfungizone, and subcultured at least four times. The cells are thenseeded in six-well plates in the same medium. Eight hours before theassay, after the cells reach confluence, the medium is replaced. Thecells are then incubated with a) medium alone, b) medium containingendothelin-1 (10 nM), c) test compound alone, and d) testcompound+endothelin-1 (10 nM).

After a 15 min incubation, the medium is removed from each well and theconcentrations of 6-keto PGF_(1α) are measured by a direct immunoassay.Prostacyclin production is calculated as the difference between theamount of 6-keto PGF_(1α) released by the cells challenged with theendothelin-1 minus the amount released by identically treatedunchallenged cells. Compounds that stimulate 6-keto PGF_(1α) releasepossess agonist activity and those which inhibit endothelin-16-ketoPGF_(1α) release possess antagonist activity.

2. Inhibition of Sarafotoxin 6c Induced Contraction

Sarafotoxin 6c is a specific ET_(B) antagonist that contracts rat fundalstomach strips. The effectiveness of tests compounds to inhibit thissarafotoxin 6c-induced contraction of rat fundal stomach strips is usedas a measure ET_(B) antagonist activity. Two isolated rat fundal stomachstrips are suspended under a 1 g load in a 10 ml organ bath filled withKrebs'—Henseleit solution containing 10 μMcyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123; see, U.S. Pat. No. 5,114,918to Ishikawa et al.), 5 μM indomethacin, and saturated with a gas mixtureof 95% O₂/5% CO₂. Changes in tension are measured isometrically andrecorded using a Grass Polygraph coupled to a force transducer.Sarafotoxin 6c is added cumulatively to one strip while the second stripis preincubated for 15 min with a test compound prior to addition ofcumulative doses of sarafotoxin 6c. The effects of the test compounds onthe concentration-response curve for sarafotoxin 6c are examined.

E. Deoxycorticosterone Acetate (DOCA)-Salt Hypertensive Rat Model forAssessing in vivo Activity of Selected Compounds

Selected compounds disclosed herein have been tested for activity in thedeoxycorticosterone acetate (DOCA)-salt hypertensive rat model. Toperform these tests, silastic MDX4-4210 elastomer implants containing 47mg (DOCA) were prepared according to the method of Ornmsbee et al.((1973) the J. Pharm. Sci. 62:255-257). Briefly, DOCA is incorporatedinto silicon rubber implants for sustained release. To prepare theimplants the DOCA is incorporated into unpolymerized silicone rubber,catalyst is added and the mixture is cast in a hemicylindrical shape.

Sprague Dawley rats (7-8 weeks old) were unilaterally nephrectomizedunder ketamine anesthesia and a DOCA-implant was placed on the leftlateral dorsal abdomen of the animal. The rats were allowed to recoverfor three weeks. During recovery they were permitted free access tonormal rat chow and 0.9% NaCl drinking solution in place of drinkingwater. The rats develop hypertension within 3 weeks.

All animals were used in the tests between 21 and 30 days post surgery.The mean arterial blood pressure in these animals ranged from 165-200 mmHg.

On the day of experimentation, catheters were inserted under brevitalanesthesia into the right femoral artery for measurement of bloodpressure, and into the right femoral vein for administration of aselected compound. The animals were placed in a restrainer and allowedto recover for a minimum of 60 min or until a steady mean arterial bloodpressure was recorded. At that time, the selected compound or controlvehicle was administered either intravenously, as a 60 minute infusion,or orally by oral gavage. Blood pressure was recorded continuously for afurther 10 h.

F. Results

The IC₅₀ for each of the compounds of the preceding Examples for ET_(A)and ET_(B) receptors has been measured. Almost all of the compounds havean IC₅₀ of less than 10 μM for either or both of the ET_(A) and ET_(B)receptors. Many of the compounds have an IC₅₀ less than about 10 μM,others have an IC₅₀ less than about 1 μM and some of the compounds havean IC₅₀ less than about 0.1 μM. A number of the compounds have an IC₅₀for ET_(A) receptors that is substantially less (10 to 100-fold or more)than for ET_(B) receptors, and, thus are selective for ET_(A) receptors.Others of the compounds, particularly the compounds in which Ar² is4-biphenyl are ET_(B) selective.

Since modifications will be apparent to those of skill in this art, itis intended that this invention be limited only by the scope of theappended claims.

We claim:
 1. A method of altering nitric oxide levels, comprisingadministering an effective amount of an endothelin antagonist, wherebynitric oxide levels are altered.
 2. The method of claim 1, wherein theendothelin antagonist is a compound or pro-drugs of the compounds orpharmaceutically acceptable salts or acids of the compounds of formula:

wherein: R is NH₂, halogen,

or is absent; Ar is selected from:

whereby nitric oxide levels are altered.
 3. The method of claim 2,wherein the compound is selected from the group consisting of compoundsin which R is in the para position.
 4. The method of claim 1, whereinthe endothelin antagonist is a compound of formula:

wherein: (a) R¹ and R² are either (i), (ii) or (iii) as follows: (i) R¹and R² are each independently selected from the group consisting of H,NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkylalkoxy,alkylhalide, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions are either straight or branched chains that containfrom 1 up to about 10 carbon atoms, and the aryl portions contain fromabout 4 to about 14 carbons; or, (ii) R¹ and R² together form—(CH₂)_(n), where n is 3 to 6; or, (iii) R¹ and R² together form1,3-butadienyl; and (b) Ar² is alkyl or is a group selected from:

wherein: (i) R³, R⁴, R⁵, R⁶, and R⁷are each independently selected fromthe group consisting of H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide,alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino,alkylthio, alkylalkoxy, alkylsulfinyl, alkylsulfonyl, aryloxy,arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl,alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted orunsubstituted amido, substituted or unsubstituted ureido, in which thealkyl, alkenyl, alkynyl portions are straight or branched chains of fromabout 1 up to about 10 carbons, and the aryl portions contain from 4 to14 carbons; R⁸, R⁹ and R¹⁰ are each independently selected from thegroup consisting of H, NH₂, NO₂ and halide; X is O, S or NR¹¹ in whichR¹¹ is selected from H, alkyl, alkylcarbonyl or formyl; and n is from 0up to about 6; or, alternatively, (ii) R⁴ and R⁷ together aresubstituted or unsubstituted 1,3-butadienyl, 1-aza-1,3-butadienyl or2-aza-1,3-butadienyl groups; and n, X, R³, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹¹are as defined in (i) above; or alternatively, (iii) R⁷ and R³ togetherare substituted or unsubstituted 1,3-butadienyl, 1-aza-1,3-butadienyl or2-aza-1,3-butadienyl groups; and n, X, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹¹are as defined in (i) above; whereby nitric oxide levels are altered. 5.The method of claim 4, wherein: (a) R¹ and R² are selected independentlyfrom the group consisting of lower alkyl, lower alkenyl, lower alkynyl,lower haloalkyl, halide, pseudohalide and H; (b) X is NR¹¹, S or O, n is0 or 1; R¹¹ is H, CH₃ or formyl; and R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰are either (i), (ii) or (ii) as follows: (i) R⁴ and R⁷ are eachindependently selected from the group consisting of H, lower alkyl, NH₂,NO₂, halide, pseudohalide; R³ is selected from the group consisting ofH, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl,aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkylalkoxy,alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynylportions are straight or branched chains of from 1 up to 6 carbons andthe aryl portions contain from 4 to 10 or 12 carbons; R⁵, R⁶, R¹⁰ are H;R¹¹ is H or CH₃; R⁸ and R⁹ are each selected independently from among H,NO₂, NH₂ and halide; or (ii) R⁴ and R⁷ together form 1,3-butadienyl,4-chloro-1,3-butadienyl, or 1-aza-1,3-butadienyl; R³ is selected fromthe group consisting of H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide,alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkylamino,alkylthio, alkylalkoxy, alkylsulfinyl, alkylsulfonyl, aryloxy,arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl,alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted orunsubstituted amido, substituted or unsubstituted ureido, where thealkyl, alkenyl, alkynyl portions are straight or branched chains of fromabout 1 up to about 5 or 6 carbons and the aryl portions contain from 1up to about 6 carbons; R⁵, R⁶, R¹⁰ are H; R¹¹ is H or CH₃; R⁸ and R⁹ areeach selected independently from among H, NO₂, NH₂ and halide; or (iii)R⁷ and R³ together form 1,3-butadienyl, 3-chloro-1,3-butadienyl or1-aza-1,3-butadienyl; R⁴ is selected from the group consisting of H,lower alkyl, NH₂, NO₂, halide, pseudohalide; R⁵, R⁶, R¹⁰ are H; R¹¹ is Hor CH₃; R⁸ and R⁹ are each selected independently from among H, NO₂, NH₂and halide.
 6. The method of claim 4, wherein: (a) R¹ and R² areindependently selected from the group consisting of H, CH₃, C₂H₅,H₂C═CH, CH≡C, Ph—O, Ph—CH₂, 4—CH₃—C₆H₄O halide, CF₃, C₂F₅, n-C₃H₇ andiso-C₃H₇; and (b) Ar² is CH₃ or is selected from

in which: X is S or O; n is 0 or 1; R¹¹ is H; and R³, R⁴, R⁷ and R⁸ areeither (i), (ii) or (iii) as follows: (i) R⁸ is H, NO₂, NH₂ or halide;R⁴ and R⁷ are each independently selected from the group consisting ofH, halide, NH₂, CF₃, Ph and CH₃; and R³ is selected from the groupconsisting of H, NHOH, NH₂, C₂H₅NH₂, (CH₃)₂NH, Ph—CH₂NH, NO₂, F, Cl, Br,I, CN, CH₃, (CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O, CH₂═CH, Ph—CH═CH, CH≡C,Ph—CH≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or(ii) R⁴ and R⁷ together form 1,3-butadienyl, 4-chloro-1,3-butadienyl, or1-aza-1,3-butadienyl; R³ is selected from the group consisting of H,NHOH, NH₂, EtNH₂, (CH₃)₂NH, Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃,(CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O, CH₂═CH, Ph—CH═CH, CH≡C, Ph—CH≡C, Ph,3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; and R⁸ is H,NO₂, NH₂ or halide; or (iii) R⁷ and R³ together form 1,3-butadienyl,3-chloro-1,3-butadienyl or 1-aza-1,3-butadienyl; R⁴ is selected from thegroup consisting of H, halide, NH₂, CF₃, Ph and CH₃; and R⁸ is H, NO₂,NH₂ or halide.
 7. The method of claim 6, wherein: Ar² is a substitutedor unsubstituted phenyl group or unsubstituted or unsubstituted naphthylgroup or a substituted or unsubstituted quinolinyl group; R¹ is Br, Cl,H, CH₃, C₂H₅, CF₃; R² is H, CH₃, C₂H₅, or CF₃; and R³, R⁴, R⁷, R⁸, R⁹,R¹⁰ and R¹¹ are either (i), (ii), (iii) or (iv) as follows: (i) R⁷, R⁸,R⁹, R¹⁰ and R¹¹ are H; n is 0 and R³ is H, NH₂, CH₃ CF₃, halide, C₂H₅NHor Ph, R⁴ is H, CF₃, NH₂; and R⁷ is H or CF₃; or (ii) R³, R⁸, R⁹, R¹⁰and R¹¹, are H; n is 0; and R⁴ and R⁷ together form 1, 3-butadienyl or4-chloro-1,3-butadienyl; or (iii) R⁴, R⁸, R⁹, R¹⁰ and R¹¹, are H; n is 0and R⁷ and R³ together form 1,3-butadienyl, 1-aza-1,3-butadienyl; or(iv) R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are H; n is 1 and R³ is H, NH₂ and halide;R⁴ is H, CF₃, NH₂; and R⁷ is H or CF₃.
 8. The method of claim 1, whereinthe endothelin antagonist is a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areeither (i), (ii) or (iii) as follows: (i) R¹ and R² are eachindependently selected from the group consisting of H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, alkyloxy, aminoalkyl, haloalkyl,alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl,arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl,aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amidoand substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions contain from 1 up to about 14 carbon atoms and areeither straight or branched chains, and the aryl portions contain fromabout 4 to about 16 carbons; or, (ii) R¹ and R² together form—(CH₂)_(n), where n is 3 to 6; or, (iii) R¹ and R² together form1,3-butadienyl; Ar² is benzene or a substituted benzene and has theformula:

in which R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or (ii) as follows: (i)R³, R⁴, R⁵, R⁶, and R⁷ are each selected independently from the groupconsisting of H, NHOH, NH₂, NO₂, pseudohalide, halide, alkenyl, alkynyl,aryl, heteroaryl, alkoxy, alkylamino, dialkylamino, aminoalkyl,alkylthio, alkylalkoxy, alkylsulfinyl, alkylsulfonyl, aryloxy,arylalkyl, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl,haloalkoxy, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl,carboxyl, hydroxyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, where the alkyl, alkenyl, alkynylportions are straight or branched chains, which are cyclic or acyclic,of from about 1 up to 10 carbons, and the aryl portions contain from 3up to about 10 carbons; (ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ areeach independently selected from the group consisting of alkyl, alkoxy,halide, amino alkyl and dialkylaminoalkyl in which the alkyl and alkoxygroups contain from 1 to 10 carbons, and are straight or branchedchains, whereby nitric oxide levels are altered.
 9. The method of claim8, wherein: R¹ and R² are selected independently from the groupconsisting of alkyl, lower alkenyl, lower alkynyl, lower haloalkyl,halide, pseudohalide and H; and R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or(ii) as follows: (i) R⁴, R⁵, R⁶ and R⁷ are each independently selectedfrom the group consisting of H, lower alkyl, NH₂, NO₂, lower alkylamino,lower dialkylamino, halide, lower haloalkyl, lower alkoxy, lowerhaloalkoxy, amino(lower)alkyl, and pseudohalide; R³ is selected from H,NHOH, NH₂,NO₂, N₃, lower alkylamino, lower dialkyl amino, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy,alkylamino, alkylthio, alkylalkoxy, alkylsulfinyl, alkylsulfonyl,aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl,haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl,substituted or unsubstituted amido and substituted or unsubstitutedureido, and the alkyl, alkenyl, alkynyl portions are straight orbranched chains of from 1 to 6 carbons and the aryl portions containfrom 3 to 14 carbons; or (ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ areeach independently selected from the group consisting of alkyl, aminoalkyl and dialkylaminoalkyl in which the alkyl groups contain from 1 to6 carbons, and are straight or branched chains.
 10. The method of claim8, wherein: R¹ and R² are independently selected from the groupconsisting of H, CH₃, C₂H₅, H₂C═CH, CH≡C, Ph—O, Ph—CH₂, 4—CH₃—C₆H₄O,halide, CF₃, C₂F₅, n-C₃H₇, iso-C₃H₇, cyclo-C₃H₇, nC₄H₉, iso-C₄H₉,tert-C₄H₉, nC₆H₁₃, nC₁₃H₂₇ and nC₉H₁₉; and R³, R⁴, R⁵, R⁶, and R⁷ areeither (i) or (ii) as follows: (i) R⁴, R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of H, halide, NH₂, CF₃,Ph,CH₃ CH₃O, NO₂; and R³ is selected from the group consisting of H,NHOH, NH₂, C₂H₅NH₂, (CH₃)₂NH, Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃,(CH₃)₂CH, (CH₃)₃C, C₅H₁₁, CH₃O, n-C₄H₉O, CH₂═CH, Ph—CH═CH, CH≡C,Ph—CH≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or(ii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are alkyl groups alkyl groupsthat contain from 1 to 3 carbons, and are straight or branched chains.11. The method of claim 8, wherein: R¹ is Br, Cl, H, CH₃, C₂H₅ or CF₃;R²is H, CH₃, C₂H₅ or CF₃; and R³, R⁴, R⁵, R⁶, and R⁷ are either (i) or(ii) as follows: (i) R³ is H. NH₂, CH₃ CF₃, halide, CH₃, (CH₃)₃C,(CH₃)₂CH or C₂H₅NH;R⁴, R⁵ and R⁶ are independently selected from H, CH₃,C₂H₅, (CH₃)₂CH, CF₃, CH₃O, F, Br, Cl and NH₂; and R⁷ is H, CH₃, CH₂CH₅,(CH₃)CH, CH₃O, F, Br, Cl, or CF₃; or (ii) R³, R⁵, and R⁷ are H; and R⁴and R⁶ are ethyl.
 12. The method of claim 1, wherein the endothelinantagonist is a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is halide; R²is selected from the group consisting of H, NH₂, alkyl, alkenyl,alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio,alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino,arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl,alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, hydroxyl,formyl, substituted or unsubstituted amido, and substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionscontain from 1 up to about 14 carbon atoms and are either straight orbranched chains or cyclic, and the aryl portions contain from about 3 toabout 16 carbons; and Ar² is substituted or unsubstituted alkyl oralkenyl in which the substituents are selected from the group consistingof H, NH₂, halide, lower alkyl, aryl, alkoxy(lower)alkyl in which thealkyl portions contain from 1 up to 14 carbon atoms and are eitherstraight or branched chains, the lower alkyl portions contain from 1 to6 carbons, and the aryl portions contain from about 3 to about 16carbons, or Ar² is a group selected from the group consisting of:

in which R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are either (i), (ii),(iii) or (iv): (i) R³, R⁴, R⁵, R⁶, and R⁷ are each selectedindependently from the group consisting of H, NHOH, NH₂, NO₂, N₃,aminoalkyl, alkylamino, dialkylamino, dialkylaminoalkyl, carboxyl,carbonyl, hydroxyl, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkoxy, alkylamino, alkylthio, alkylalkoxy, alkylsulfinyl,alkylsulfonyl, aryloxy, arylalkoxy, aryloxy, arylamino, arylthio,arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, haloalkoxy,alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted orunsubstituted amido, substituted or unsubstituted ureido in which thealkyl, alkenyl, alkynyl portions are straight or branched chains of from1 up to 10 carbons and the aryl portions contain from 3 to 10 carbons;R⁸, R⁹ and R¹⁰ are each independently selected from H, NH₂, NO₂ andhalide; X is O, S or NR¹¹ in which R¹¹ is H, alkyl, alkylcarbonyl orformyl; and n is from 0 up to about 6; or, alternatively, (ii) R⁴ and R⁷together are substituted or unsubstituted 1, 3-butadienyl,4-dimethylamino-1,3 butadiene, 1-chloro-1,3-butadiene,4-dimethylamino-1,3-butadienyl, 1-aza-1,3-butadienyl or2-aza-1,3-butadienyl groups; and n, X, R³, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹¹are as defined in (i) above; or alternatively, (iii) R⁷ and R³ togetherare substituted or unsubstituted 1,3-butadienyl,4-dimethylamino-1,3butadiene, 1-chloro-1,3-butadiene,4-dimethylamino-1,3-butadienyl, 1-aza-1,3-butadienyl or2-aza-1,3-butadienyl groups; and n, X, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹¹are as defined in (i); or alternatively (iv) R³, R⁵, and R⁷ are H; andR⁴ and R⁶ are each independently selected from the group consisting ofalkyl, alkoxy, halide, amino alkyl and dialkylaminoalkyl in which thealkyl and alkoxy groups contain from 1 to 10 carbons, and are straightor branched chains; and R⁸, R⁹, R¹⁰ and R¹¹ are as defined in (i),whereby nitric oxide levels are altered.
 13. The method of claim 12,wherein R¹ is Br or Cl; R² is selected from the group consisting ofalkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide,pseudohalide and H; n is 0 or 1; and R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ andR¹¹ are either (i), (ii), (iii), or (iv): (i) R⁴ and R⁷ are eachindependently selected from the group consisting of H, lower alkyl, NH₂,NO₂, halide, pseudohalide; and R³is selected from the group consistingof H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl,aryl, heteroaryl, alkoxy, alkylamino, dialkylamino, dialkylaminoalkyl,alkylthio, alkylalkoxy, alkylsulfinyl, alkylsulfonyl, aryloxy,arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl,alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, substituted andunsubstituted amido, substituted or unsubstituted ureido, in which thealkyl, alkenyl, alkynyl portions are straight or branched chains of from1 up to 6 carbons and the aryl portions contain from 3 to 6 carbons; R⁵,R⁶, R¹⁰ are H; R¹¹ is H or CH₃; R⁸ and R⁹ are each selectedindependently from the group consisting of H, NO₂, NH₂ and halide; or(ii) R⁴ and R⁷ together form 1, 3-butadienyl, 4-chloro-1,3-butadienyl,4-dimethylamino-1,3-butadienyl, or 1-aza-1,3-butadienyl; and R³, R⁵, R⁶,R⁸, R⁹, R¹⁰ and R¹¹ are defined as in (i) of this embodiment; or (iii)R⁷ and R³ together form 1,3-butadienyl, 3-chloro-1,3-butadienyl,4-dimethylamino-1,3-butadienyl, or 1-aza-1,3-butadienyl; and R⁴, R⁵, R⁶,R⁸, R⁹, R¹⁰ and R¹¹ are as defined in (i); (iv) R³, R⁵, and R⁷ are H;and R⁴ and R⁶ are each independently selected alkyl, amino alkyl anddialkylaminoalkyl in which the alkyl and alkoxy groups contain from 1 to6 carbons, and are straight or branched chains; and R⁸, R⁹, R¹⁰ and R¹¹are as defined in (i).
 14. The method of claim 12, wherein R² isselected from the group consisting of H, CH₃, C₂H₅, H₂C═CH, CH≡C, Ph—O,Ph—CH₂, 4-CH₃—C₆H₄O, halide, CF₃, C₂F₅, n-C₃H₇, iso-C₃H₇, nC₁₃H₂₇ andnC₉H₁₉; R¹ is Cl or Br; X is NH, O or S; n is 0 or 1; and R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are either (i), (ii), (iii) or (iv): (i) R⁸and R⁹ are H, NO₂, NH₂ or halide; R⁵, R⁶ and R¹¹ are H; R⁴ and R⁷ areeach independently selected from the group consisting of H, halide, NH₂,CF₃, Ph, CH₃; and R³ is selected from the group consisting of H, NHOH,NH₂, EtNH₂, (CH₃)₂NH, Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃, (CH₃)₃C,C₅H₁₁, CH₃O, n-C₄H₉O, CH₂═CH, Ph—CH═CH, CH≡C, dimethylaminomethyl,Ph—CH≡C, Ph, 3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; or(ii) R⁴ and R⁷ together form 1, 3-butadienyl, 4-chloro-1,3-butadienyl,4-diamino-1,3-butadienyl or 1-aza-1,3-butadienyl; and R³, R⁵, R⁶, R⁸,R⁹, R¹⁰ and R¹¹ are defined as in (i); or (iii) R⁷ and R³ together form1,3-butadienyl, 3-chloro-1,3-butadienyl, 4-diamino-1,3-butadienyl or1-aza-1,3-butadienyl; and R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and R¹¹ are as definedin (i); or (iv) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are eachindependently selected from the group consisting of alkyl and aminoalkylgroups in which the alkyl groups contain from 1 to 6 carbons, and arestraight or branched chains; and R⁸, R⁹, R¹⁰ and R¹¹ are as defined in(i).
 15. The method of claim 12, wherein R¹ is Br or Cl; R² is H, CH₃,C₂H₅, H₂C═CH, CH≡C, Ph—O, Ph—CH₂, 4-CH₃-C₆H₄O, halide, CF₃, C₂F₅,n-C₃H₇, iso-C₃H₇, nCl₃H₂₇ and nC₉H₁₉; and Ar² is a substituted orunsubstituted phenyl group; and R³, R⁴, R⁵, R⁶ and R⁷ are either (i),(ii) or (iii): (i) R⁵, R⁶ and R⁷ are H; n is 0; R³ is H, NH₂, CH₃ CF₃,halide, C₂H₅NH or Ph; R⁴ is H, CF₃, NH₂; R⁷ is H or CF₃; and R⁵ and R⁶are H; or (ii) n is 1; R³ is H, NH₂ or halide; R⁴ is H, CH₃, Br, Cl, F,CF₃, NH₂, R⁷ is H, CH₃, Br, Cl, F, NH₂ or CF₃; and R⁵ and R⁶ are H; or(iii) R³, R⁵, and R⁷ are H; and R⁴ and R⁶ are each independentlyselected from the group consisting of alkyl groups that contain from 1to 3 carbons.
 16. The method of claim 12, wherein R¹ is Br or Cl; R² isH, CH₃, C₂H₅, C₂F₅ or CF₃; and Ar² is a substituted or unsubstitutednaphthyl group or thianaphthyl group in which and R³, R⁴, R⁵, R⁶ and R⁷are either (i) or (ii): (i) R³, R⁵ and R⁶ are H; n is 0 and R⁴ and R⁷together form 1,3-butadienyl, 4-dimethylamino-1,3 butadiene,1-chloro-1,3-butadiene, or 4-chloro-1,3-butadienyl; or (ii) R⁴, R⁵, R⁶,R⁸, R⁹, R¹⁰ and R¹¹ are H; n is 0; and R⁷ and R³ together form1,3-butadienyl, 4-dimethylamino-1,3 butadiene, 1-chloro-1, 3-butadiene,1-aza-1,3-butadienyl.
 17. The method of claim 12, wherein R¹ is Br orCl; R² is selected from the group consisting of H, CH₃, C₂H₅, H₂C═CH,CH≡C, Ph—O, Ph—CH₂, 4-CH₃—C₆H₄O, halide, CF₃, C₂F₅, n-C₃H₇, iso-C₃H₇ andC₄H₉; and Ar² is selected from the group consisting of substituted orunsubstituted thiophenes, furans, a pyrroles, indoles, benzofurans,quinolines, isoquinolines, styrenes and thianaphthalenes in which R¹ isCl or Br; X is NH, O or S; n is 0 or 1; in (i) R⁸ and R⁹ are H, NO₂, NH₂or halide; R⁵, R⁶ and R¹¹ are independently selected from the groupconsisting of H, CF₃, halide, Cl and NH₂; R⁴ and R⁷ are eachindependently selected from the group consisting of H, halide, NH₂, CF₃,Ph, CH₃; and R³ is selected from the group consisting of H, NHOH, NH₂,EtNH₂, (CH₃)₂NH, Ph—CH₂NH, NO₂, F, Cl, Br, I, CN, CH₃, (CH₃)₃C, C₅H₁₁,CH₃O, n-C₄H₉O, CH₂═CH, Ph—CH═CH, CH≡C, Ph—CH≡C, Ph,3-(ethyoxycarbonylmethyl)ureido, and 3-cyclohexylureido; and in (iv) R³,R⁵, and R⁷ are H; and R⁴ and R⁶ are each independently selected from thegroup consisting of alkyl and aminoalkyl groups in which the alkylgroups contain from 1 to 6 carbons, and are straight or branched chains;and R⁸, R⁹, R¹⁰ and R¹¹ are as defined in (i).
 18. The method of claim17, wherein R² is H, CH₃, C₂H₅, or CF₃; in (i) R³ is H, NH₂, CH₃ CF₃,halide or C₂H₅NH; R⁴, R⁵ and R⁶ are H; R⁷ is selected from the groupconsisting of H, CH₃, CH₂CH₅, (CH₃)CH, F or CF₃, and R⁸, R⁹ and R¹⁰ areindependently selected from the group consisting of H, NO₂, NH₂ orhalide; and R¹¹ is H; and in (iv) R³, R⁵, and R⁷ are H; and R⁴ and R⁶are each independently selected from the group consisting of alkylgroups that contain from 1 to 3 carbons, and are straight or branchedchains; and R⁸, R⁹, R¹⁰ and R¹¹ are as defined in (i).
 19. The method ofclaim 1, wherein the endothelin antagonist is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is halide; R²is selected from the group consisting of H, NH₂, alkyl, alkenyl,alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio,alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino,arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl,alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, hydroxyl,formyl, substituted or unsubstituted amido, and substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionscontain from 1 up to about 14 carbon atoms and are either straight orbranched chains or cyclic, and the aryl portions contain from about 3 toabout 16 carbons; and Ar² is alkenyl, biphenyl, quinolyl, styryl,isoquinolyl, indolyl or thianaphthyl, whereby nitric oxide levels arealtered.
 20. The method of claim 19, wherein Ar² is biphenyl.
 21. Themethod of claim 1, wherein the endothelin antagonist is a compound offormula:

wherein: Ar¹ is a substituted or unsubstituted group, containing from 1to 30 carbon atoms, selected from the group consisting of alkyl, alkenyland alkynyl groups, which may be straight or branched chains or includecyclic portions, aryl groups, heterocyclic rings and fused bicyclic ortricyclic rings; and Ar² is a substituted or unsubstituted groupselected from thiophenyl, furyl and pyrrolyl, whereby nitric oxidelevels are altered.
 22. The method of claim 21, wherein Ar¹ is alkyl oris selected from the group consisting of the following groups:

that are unsubstituted or substituted with one or more substituents R,which are each independently selected from the group consisting of H,NH₂, halide, pseudohalide, alkyl alkylcarbonyl, formyl, an aromatic orheteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl,aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in whichthe aryl and alkyl portions, are unsubstituted or substituted, the alkylportions are straight or branched chains of from about 1 up to about10-12 carbons, and the aryl portions are substituted or unsubstitutedand contain from 3 to about 14 carbon atoms.
 23. The method of claim 21,wherein Ar¹ is an isoxazolyl group.
 24. The method of claim 23, whereinthe compound has the formula:

wherein R¹ and R² are selected from (i), (ii) or (iii): (i) R¹ and R²are each independently selected from the group consisting of H, NH₂,NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl,heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl,alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl,arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl,aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions contain from 1 up to about 14 carbon atoms and areeither straight or branched chains or cyclic, and the aryl portionscontain from about 4 to about 16 carbons; or, (ii) R¹ and R² togetherform —(CH₂)_(n), where n is 3 to 6; or, (iii) R¹ and R² together form1,3-butadienyl.
 25. The method of claim 24, wherein Ar² is thiophenyl.26. The method of claim 24, wherein Ar² is furyl.
 27. The method ofclaim 24, wherein Ar² is pyrrolyl.
 28. The method of claim 24, whereinthe compound has the formulae:

wherein: X is O, S, NH or NR¹¹ in which R¹¹, which is hydrogen orcontains up to about 30 carbon atoms, is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R¹⁵ and S(O)_(n)R¹⁵ in which n is 0-2; and R¹⁵, which is selectedindependently from R¹¹ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; and R⁸, R⁹and R¹⁰ are selected from (i) or (ii): (i) R⁸, R⁹ and R¹⁰, which eachcontain hydrogen or up to about 50 carbon atoms, are each independentlyselected from the group consisting of hydrogen, halide pseudohalide,alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸,CO₂R¹⁸, SH, S(O)_(n)R¹⁸ in which n is 0-2, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸,R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸, in which R¹⁹ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R²⁰ and S(O)_(n)R²⁰ in which n is 0-2;and R¹⁸ and R²⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, alkoxy, aryloxy, alkoxy, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl or cycloalkynyl; or (ii) any two of R⁸, R⁹ and R¹⁰ form anaromatic or heteroaromatic ring or an alicyclic or heterocyclic ring,which is saturated or unsaturated, containing from about 3 to about 16members, and the other of R⁸, R⁹ and R¹⁰ is selected as in (i); whereR⁸, R⁹, and R¹⁰ may be further substituted with one or more substituentsselected from Z, which is selected from the group consisting ofhydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ in which n is 0-2, NHOH,NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶ and CONR¹²R¹⁶; R¹⁶ is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl; R¹² is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁷ andS(O)_(n)R¹⁷ in which n is 0-2; and R¹⁷ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl.
 29. The method of claim 28, wherein X is S.
 30. The methodof claim 28, wherein X is O.
 31. The method of claim 28, wherein X is N.32. The method of claim 28, wherein at least two of R⁸, R⁹ and R¹⁰hydrogen, halogen or lower alkyl, and the other is C(O)R¹⁸, CO₂R¹⁸,NR¹⁸R¹⁹, R¹⁹NCOR¹⁸, or CONR¹⁹R¹⁸; where R¹⁸ is phenyl and R¹⁹ is H orlower alkyl.
 33. The method of claim 32, wherein R¹ is Br or Cl or loweralkyl and R² is lower alkyl, lower haloalkyl, or hydrogen.
 34. Themethod of claim 21, wherein the compound is selected from the groupconsisting ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylcarboxamide)thiophene-3-sulfonamide;N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylcarboxamide)thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)carboxamide]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)carboxamide]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(benzylcarboxamide]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)carboxamide]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-LN-(3-methoxyphenyl)carboxamidelthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)carboxamide]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzenesulfonylthiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]}thiophene-5-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)carboxamide]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)carboxamide]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-5-thienylthiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide,N-(4-bromo-5-methyl-3-isoxazolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-3-methoxy-2-thiophene sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-1-5 thiophene sulfonamide,and N-(4-bromo-3-methyl-5-isoxazolyl)4-phenyl-2-thiophene sulfonamide.35. The method of claim 1, wherein the endothelin antagonist is acompound of formula:

wherein, which R¹ and R² are either (i), (ii) or (iii) as follows: (i)R¹ and R² are independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, haloalkoxy,haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio,arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted orunsubstituted amido, substituted or unsubstituted ureido, in which thealkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbonatoms and are either straight or branched chains or cyclic, and the arylportions contain from about 4 to about 16 carbons, with the proviso thatR²is not halide or pseudohalide; or, (ii) R¹ and R² together form—(CH₂)_(n), where n is 3 to 6; or, (iii) R¹ and R² together form1,3-butadienyl; and Ar² is thienyl, furyl, pyrrolyl, benzofuryl,thianaphthyl or indolyl, whereby nitric oxide levels are altered. 36.The method of claim 35, wherein the compound has the formulae:

in which R¹, R², are either (i), (ii) or (iii) as follows: (i) R¹ and R²are each independently selected from H, NH₂, NO₂, halide, pseudohalide,alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy,alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl,aminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl,arylcarbonyl, formyl, substituted or unsubstituted amido, substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionsare either straight or branched chains that contain from 1 up to about10 carbon atoms, and the aryl portions contain from about 4 to about 14carbons, except the R² is not halide, pseudohalide or higher alkyl; or,(ii) R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or, (iii) R¹and R² together form 1,3-butadienyl; and X is O, S, N or NR¹¹, whereR¹¹, which is hydrogen or contains up to about 30 carbon atoms, and isselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R¹⁵ and S(O)_(n)R¹⁵ in which n is 0-2; R¹⁵ is hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl; R¹¹ and R¹⁵ are unsubstituted orare substituted with one or more substituents each selectedindependently from Z, which is halide, pseudohalide, alkyl, alkoxy,alkenyl, alkynyl, aryl, heterocycle, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ inwhich n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶ and CONR¹²R¹⁶;R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R¹², whichis selected independently from R¹¹ and Z, is selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁷ andS(O)_(n)R¹⁷ in which n is 0-2; and R¹⁷ is hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl or cycloalkynyl; each of R¹¹, R¹², R¹⁵ and R¹⁶ may befurther substituted with the any of the groups set forth for Z; and R⁸,R⁹, R¹⁰ are each independently selected as follows from (i) or (ii): (i)R⁸, R⁹ and R¹⁰, which each contain hydrogen or up to about 50 carbonatoms, generally up to about 30, more generally 20 or fewer, are eachindependently selected from hydrogen, halide, pseudohalide, alkyl,alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸, CO₂R¹⁸, SH,S(O)_(n)R¹⁸ in which n is 0-2, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸l R¹⁹NCOR¹⁸and CONR¹⁹R¹⁸, in which R¹⁹ is selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²⁰, S(O)_(n)R²⁰in which n is 0-2; and R¹⁸ and R²⁰ are independently selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy,aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl orureido; and any of the groups set forth for R⁸, R⁹ and ¹⁰ areunsubstituted or substituted with any substituents set forth for Z,which is halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl,aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)^(n)R²¹ in which n is0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ and CONR²²R²¹; R²² isselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, C(O)R²³ and S(O)_(n)R²³ in which n is 0-2; and R²¹ and R²³are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; or (ii) any two of R⁸, R⁹ and R¹⁰ form an aryl, aromaticring, heteroaromatic ring, alicyclic or heterocyclic ring, which issaturated or unsaturated, containing from about 3 to about 16 members,more preferably 5 to 7 members that is unsubstituted or substituted withone or more substituents in each substituent is independently selectedfrom Z; and the other of R⁸, R⁹ and R¹⁰ is selected as in (i).
 37. Themethod of claim 36, wherein Ar² is thienyl.
 38. The method of claim 36,wherein Ar² is furyl.
 39. The method of claim 36, wherein Ar2 ispyrrolyl.
 40. The method of claim 36, wherein R¹ is H, lower alkyl,halide or pseudohalide; and R² is lower alkyl, lower alkenyl, loweralkynyl, lower haloalkyl, halide, pseudohalide or hydrogen.
 41. Themethod of claim 36, wherein at least two of R⁸, R⁹ and R¹⁰ hydrogen,halogen or lower alkyl, and the other is C(O)R¹⁸, CO₂R¹⁸, NR¹⁸R¹⁹,R¹⁹NCOR¹⁸ or CONR¹⁹R¹⁸; where R¹⁸ is phenyl and R¹⁹ is H or lower alkyl.42. The method of claim 41, wherein R¹ is Br or Cl or alkyl and R² islower alkyl, lower haloalkyl, or hydrogen.
 43. The method of claim 36,wherein the compound is selected from the group consisting ofN-(4-bromo-3-methyl-5-isoxazolyl)-[N-(4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phentio)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-5-methyl-3-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-tolulylaminocarbonylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-t-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-butylphenyl)aminocarbonylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide;3-phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide;4-phenethyl-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzenesulfonyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]}thiophene-5-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-thienylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(phenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-styrylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-styrylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenoxythiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzenesulfonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamino)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-phenyl)methylaminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylfuran-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(hydroxymethyl)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(carbomethoxy)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylfuran-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(dimethylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(di-iso-propylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diethylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-iso-butylphenyl)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylfuran-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)2-thiophenesulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dimethylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-5-methyl-3-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl)thiophene-3-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methylphenyl)arninocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyi)-2-[N(4-t-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-n-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide;andN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-se-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3methyl-5-isoxazolyl)-2-[N-(4-setyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)-thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)2-thiophenesulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-[N-(4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide;andN-(4-chloro-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide.